The Latest topics of Standards of Care in Diabetes 2025: Focusing on GLP-1RA

Asploro Journal of Biomedical and Clinical Case Reports

ISSN: 2582-0370
Article Type: Commentary
DOI: 10.36502/2024/ASJBCCR.6386
Asp Biomed Clin Case Rep. 2024 Dec 31;8(1):34-37

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Hiroshi Bando^1,2iD*, Michael Wood², Koji Ebe^2,3
¹Medical Research/Tokushima University, Tokushima, Japan
²Japan Low Carbohydrate Diet Promotion Association (JLCDPA), Kyoto, Japan
³Takao Hospital, Kyoto, Japan

Corresponding Author: Hiroshi Bando ^{ORCID iD}
Address: Tokushima University /Medical Research, Nakashowa 1-61, Tokushima 770-0943, Japan.
Received date: 13 December 2024; Accepted date: 26 December 2024; Published date: 31 December 2024

Citation: Bando H, Wood M, Ebe K. The Latest topics of Standards of Care in Diabetes 2025: Focusing on GLP-1RA. Asp Biomed Clin Case Rep. 2024 Dec 31;8(1):34-37.

Copyright © 2024 Bando H, Wood M, Ebe K. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

Keywords: American Diabetes Association, Standards of Care in Diabetes-2025, Glucagon-like Peptide-1 Receptor Agonist, Alzheimer Disease, Parkinson’s Disease

Abbreviations: ADA: American Diabetes Association; GLP-1RA: Glucagon-like Peptide-1 Receptor Agonist; AD: Alzheimer Disease; PD: Parkinson’s Disease

Abstract

The American Diabetes Association (ADA) presented the Standards of Care in Diabetes-2025 online in December 2024. The authors immediately reviewed and provided perspectives on the latest developments regarding glucagon-like peptide-1 receptor agonists (GLP-1RA). Some newly added content about GLP-1RA is included, such as its application for heart failure with preserved ejection fraction (HFpEF), obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH). Concurrent use of DPP-4 inhibitors (DPP-4i) with GLP-1RA (GIP/GLP-1RA) is not recommended due to a lack of additional glucose-lowering effects beyond GLP-1RA alone. GLP-1RA is expected to demonstrate various positive clinical effects.

Commentary

The American Diabetes Association (ADA) Standards of Care (SoC) in Diabetes-2025 was published online in December, and the authors immediately reviewed it in detail. Chapter 9, Pharmacologic Approaches to Glycemic Treatment, particularly highlights the growing attention GLP-1 receptor agonists (GLP-1RA) have received in recent years [1].

The standard usage of GLP-1RA is described in sections 9.24–26 [2]. The key points are summarized as follows:
i) For cases with type 2 diabetes (T2D) and no evidence of insulin deficiency, GLP-1RA (dual GIP/GLP-1RA) is preferred over insulin (A).
ii) If insulin is used, the recommended treatment is a combination with GLP-1RA or GIP/GLP-1RA, which demonstrates greater effectiveness with benefits on weight and hypoglycemic risk in T2D (A).
iii) For adults with T2D who are starting insulin, glucose-lowering agents should be continued to maintain glycemic and metabolic benefits, including cardiometabolic, renal, and weight benefits (A) [3].

In this chapter, various recommendations are provided. Among them, newly added content includes the following:

i) For T2D patients with symptomatic heart failure with preserved ejection fraction (HFpEF) and obesity, GLP-1RA is recommended for its beneficial effects on glycemic control and reduction of HF-related symptoms (A).
ii) For adults with T2D and MASLD (overweight or obesity), GLP-1RA (GLP/GIP-GLP-1RA) is recommended for its potential benefits in managing MASH or glycemic control as an adjunctive intervention for weight reduction (B).
iii) For T2D patients with MASH (biopsy-proven, high-risk fibrosis), pioglitazone or GLP-1RA (GIP/GLP-1RA) is preferred for glycemic control due to its potential beneficial effects on MASH (B) [4].
iv) Concurrent use of DPP-4 inhibitors (DPP-4i) with GLP-1RA (GIP/GLP-1RA) is not recommended due to a lack of additional glucose-lowering effects beyond GLP-1RA alone (B) [3,5].

GLP-1RAs are known for their efficacy in weight reduction for obesity, overweight, and diabetes [6]. This mechanism involves several pathways, including decreased water retention, weight reduction, and improved heart failure symptoms [7]. Consequently, GLP-1RA appears to exhibit various pharmacophysiological mechanisms [8]. Their clinical effects are summarized in Fig-1, highlighting three primary functions: anti-brain effects, anti-inflammation, and glucose control. Through these mechanisms, GLP-1RA may potentially treat conditions such as Alzheimer’s disease, Parkinson’s disease, MASLD, CKD, diabetes, cardiovascular disease, and obesity.

Fig-1: Various Clinical Effects of GLP-1RA

The Latest topics of Standards of Care in Diabetes 2025: Focusing on GLP-1RA

GLP-1RA has shown potential benefits for Alzheimer’s disease (AD) and other neurological, psychological, and metabolic disorders [9]. It may also delay the onset of Parkinson’s disease (PD) [10]. Notably, exenatide, a GLP-1RA, has demonstrated anti-inflammatory effects via microglia activation for PD [11]. In a protocol involving 447 cases divided into three groups (2.5 mg, 5.0 mg of NLY01, and placebo), total scores on the MDS-UPDRS Part 2 and 3 showed no significant changes. However, a subgroup indicated probable motor benefits in younger participants.

GLP-1RAs have also been shown to reduce the risk of death, stroke, and heart attack in patients with cardiovascular disease and CKD [12]. Obese and T2D patients exhibit a higher prevalence of HFpEF. Comparative evaluations of semaglutide versus placebo groups revealed improvements in KCCQ-CSS scores (13.7 vs. 6.4 pts) and weight reduction ratios (-9.8% vs. -3.4%) [13]. Additionally, the FLOW trial reported a 24% lower primary outcome risk for the semaglutide group (HR 0.76), with kidney-specific outcomes (HR 0.79) and cardiovascular death (HR 0.71) also favoring semaglutide [14].

GLP-1RAs may also benefit conditions like sleep apnea syndrome (SAS), MASLD, and HIV-related complications. Moreover, they could reduce addictions to substances such as alcohol and tobacco, with several clinical trials currently underway [15]. The underlying mechanisms involve GLP-1’s dual action pathways. The first pathway acts on the intestinal tract, where intestinal mucosa cells produce GLP-1, stimulating pancreatic insulin secretion and slowing digestion, leading to appetite suppression. The second pathway acts on the brain, regulating appetite, mood, and reward-related behavior.

Synthetic GLP-1RAs, such as semaglutide and tirzepatide, maintain higher blood concentrations and exhibit longer-lasting effects compared to natural GLP-1, potentially increasing their ability to reach the brain [16,17]. Unlike previous anti-obesity drugs, GLP-1RAs target both peripheral organs and brain receptors, offering broader clinical applications. However, it remains unclear to what extent GLP-1RAs penetrate the blood-brain barrier (BBB) in humans. While animal studies suggest that some GLP-1RAs can cross the BBB [18], others, like semaglutide, may not penetrate the BBB as effectively in humans [19].

Regarding GLP-1RAs’ potential effects on the reward system, studies indicate they consistently decrease energy intake and influence reward-related behavior. This is linked to reduced neuro-cortical activation in response to high-reward food cues and lower calorie intake. GLP-1RAs may address reward dysfunctions related to food stimuli, T2D, and obesity. They also improve insulin resistance and may reduce anhedonia, making them potentially applicable to addiction disorders [20].

In summary, this commentary highlights the latest advancements in GLP-1RA, including the ADA SoC-2025 and its wide-ranging positive effects. GLP-1RAs influence neural pathways that control reward, taste, and salience, offering promising possibilities in medical and healthcare applications.