In the medical practice for diabetes, recent topics include various benefits of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Among them, semaglutide has been known for its dual routes of injection and oral hypoglycemic agent (OHA). In latest report, a study of semaglutide was conducted concerning bone formation marker of Procollagen type I N-terminal propeptide (PINP) in the elderly with higher fracture risk [1]. Participants were divided into semaglutide p and placebo groups followed for 52 weeks. Former group showed higher value of p-cross-linked C-terminal telopeptide (p-CTX) and lower value of lumbar spine and total hip areal bone mineral densities (aBMD). From these findings, bone formation did not increase, which may be due to accompanying weight reduction.

From another latest impressive report, the possible increase of nonarteritic anterior ischemic optic neuropathy (NAION) was presented [2]. The methods included 16,827 cases without NAION history, and matched cohort study for T2D, weight, semaglutide or non-GLP-1RA medications. As a result, the cumulative incidence for NAION in semaglutide vs non-GLP-1RA groups showed 8.9% vs 1.8%. From Cox proportional hazards, the former group showed hazard ratio (HR) 4.28. In the case of overweight or obesity, HR showed 7.64 by a cox proportional hazard regression model. From these data, relationship between semaglutide and NAION may be present.

Lixisenatide has been one of GLP-1RAs that has presented the neuroprotective properties in a mouse model of Parkinson's Disease (PD). As funded by the French Ministry of Health and others, Trial of Lixisenatide in Early Parkinson's Disease (LIXIPARK) has been conducted by LIXIPARK Study group [3]. The study type was phase 2, double-blind, randomized placebo-controlled trial, associated with totally 156 cases of 78 assigned to each group. They used the scores of the movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS). As a result for 12 months later, the scale score showed 0.04 points improvement in lixisenatide group and 3.04 points aggravation in placebo group. Further larger evaluation will be required for judgement of clinical effect, gastrointestinal adverse effect (GI-AE), and safety.

Another related report is found. The longer-lasting exenatide has been believed to have anti-inflammatory effect through microglia activation for PD. From 447 cases, 255 eligible participants were randomly assigned to 3 groups with 2.5mg, 5.0mg of NLY01, and placebo [4]. As a result, sum scores on MDS-UPDRS parts II and III did not show significant changes among 3 groups. However, subgroup analysis brought the possible motor benefit for younger cases.

Type 2 diabetes (T2D) and obese cases show higher prevalence of heart failure with preserved ejection fraction (HFpEF). Comparative study was conducted for these patients for two groups of semaglutide and placebo for 52 weeks [5]. As the primary end points, the changes of score ranges of Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) were used. Secondary end points included the changes of 6-minute walk distance. As a result, 616 cases were included for randomization. The mean changes in KCCQ-CSS showed 13.7 pts vs 6.4 pts in semaglutide vs placebo group, and weight reduction ratio was -9.8% vs -3.4% in two groups. Thus, semaglutide brought larger reductions for clinical symptoms, greater weight reduction than placebo for 1 year.

For the clinical efficacy of semaglutide, some researchers have raised some inquiries for other etiologies [6,7]. They include certain relationships among weight reduction, decreased water retention, improvement of heart failure, or the differences of pharmacological mechanism of SGLT2-i. There may be possible different functioning pathway, which can improve the etiology of heart failure.

Concerning the risk for thyroid cancer in T2D, investigation was performed to clarify the involvement of GLP-1RAs or DPP4-i [8]. The first cohort analyzed 21,722 new cases for GLP-1RAs and 326,993 new cases for SGLT2-i. Further, the second cohort analyzed DPP4-i new cases and SGLT2-i new users. The outcomes indicated the time until the incident thyroid cancer. GLP-1RAs did not show increased risk of thyroid cancer as HR of 0.98. DPP4-i was not also related with increased risk of thyroid cancer as HR 0.95 in comparison with SGLT2-i. There was no significant efficacy modification by subgroup analyses.

Each country has recently issued guidelines for T2D. In Japan, the top three agents for obese T2D are biguanides, SGLT2-i, and GLP-1RAs, while for non-obese people, the top three are DPP4-i, biguanides, and α-glucosidase inhibitors (α-GI). As the noteworthy result, it evaluates SGLT2-i and GLP-1RA as additional benefits for chronic kidney disease (CKD), heart failure, and cardiovascular disease (CVD). In Europe and United States, the algorithm of the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) has been announced. The American College of Clinical Endocrinologists' (ACCE) consensus statement already describes different algorithms for each of the following categories [9]. They are 1) cardiorenal risk reduction or complications-centric algorithm, when the treatment goal is to focus on preventing complications and 2) glycemic and weight management or glucose-centric algorithm, when the treatment goal is to focus on blood sugar and weight management. In both categories, SGLT2-i and GLP-1RA are listed as the first-choice drugs [10].

In the most recent report, the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial, a renal outcomes trial, was terminated due to favorable results from an interim analysis. The protocol included the cases of T2D and CKD with eGFR of 50-75 mL/min/1.73², and with eGFR of 25-50 mL/min/1.73², with 2 groups of semaglutide and placebo [11]. The study was followed in 3.4 years in average. As a result, primary outcome event was 24% lower in semaglutide group (HR 0.76), with kidney-specific outcome (HR 0.79) and cardiovascular death (HR 0.71). As secondary outcomes, mean annual eGFR slope was less steep by 1.16mL/min/1.73² in semaglutide group (p<0.001) with lower cardiovascular events (HR 0.82) and major cardiovascular events (HR 0.82). Consequently, semaglutide brought risk reduction for clinically kidney outcomes and death from cardiovascular causes.

In summary, GLP-1RA seems to have beneficial effect on not only T2D/obesity, but also PD, Alzheimer disease (AD), and metabolic, neurological and psychological diseases [12]. They include depression, addiction, heart failure, and so on.  This article becomes hopefully useful reference in the future clinical research and pharmacology.

Author declares there are no conflicts of interest.

Funding: None

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