Expert Opinion on the Use of Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes and Established or High-risk Atherosclerotic Cardiovascular Disease in Thailand

In 2021, the International Diabetes Federation (IDF) reported that 537 million adults worldwide were living with diabetes, with this number predicted to rise to 643 million and 783 million by 2030 and 2045, respectively.¹ The IDF highlighted that 60% of individuals with diabetes are located in Asia.¹ The age-adjusted diabetes prevalence among individuals aged 20–79 years in Thailand was 9.7%. Type 2 diabetes (T2D) is the most prevalent type of diabetes.¹

Cardiovascular disease (CVD) is the most prominent cause of morbidity and mortality among patients with T2D.² Patients with diabetes have a 2–3 times higher cardiovascular (CV) risk than those without diabetes.²

Data from a cohort of patients with a high risk for cardiovascular events (the CORE-Thailand Registry) show that 83.8% of patients who had established atherosclerotic CVD (ASCVD) and multiple CV risk factors have either diabetes or impaired fasting glucose.³

A cross-sectional study in Thailand demonstrated a significant rising trend in the predicted 10-year CVD risk among patients with T2D, increasing from 67.2% in 2014 to 73.1% in 2018.⁴ Treatment has been found to cost more in diabetic patients with complications than in those without; the cost of treatment is about seven times higher for CV death among the former compared to the latter.⁵

Emerging therapeutic options have shown promising CV benefits for individuals with T2D and CV risk factors. The American Diabetes Association (ADA) 2025 guidelines recommended the use of either glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have proven CV benefits, or sodium-glucose cotransporter 2 inhibitors (SGLT2Is) for T2D patients with ASCVD or indicators of high-risk ASCVD (age >55 years and having two or more risk factors (e.g. obesity, hypertension, smoking, dyslipidaemia or albuminuria).⁶

Data from CV outcome trials have also demonstrated that GLP-1 RAs can reduce atherosclerotic events, particularly in patients with established or a high risk of CVD.⁷

Despite the growing evidence of the CV benefits of GLP-1 RAs and dual glucose-dependent insulinotropic polypeptide (GIP) receptor agonists/GLP-1 RAs in T2D patients and their inclusion in guidelines, lack of awareness of the CV benefits of GLP-1 RAs and dual GIP/GLP-1 RAs, clinical inertia, resistance to injectable medications and concerns about treatment costs have hindered the widespread adoption of GLP-1 RAs.⁸

This article aims to address and bridge gaps in awareness and treatment with GLP-1 RAs in Asia, including Thailand, offering insights from experts in cardiology and endocrinology in Thailand. The unfulfilled needs in the management of GLP-1 RAs among patients with T2D and established or high risk of ASCVD that are considered within this paper include:

• assessment and categorisation of CV risk among patients with T2D;
• treatment targets for patients with T2D and established or high-risk CVD;
• GLP-1 RAs for the treatment of patients with T2D and established or high risk CVD; and
• practical and safety considerations for the use of GLP-1 RAs.

Assessment and Categorisation of Cardiovascular Risk in Diabetes

Various definitions of CV risk have been proposed in multiple guidelines. This expert opinion adopts the definitions from the European Society of Cardiology (ESC) and ADA guidelines, which were used as the main sources of guidance.^6,9 Individuals with T2D should be categorised into different CV risk groups (Table 1).

The ESC 2023 guidelines introduced the SCORE2-Diabetes algorithm to estimate the 10-year CVD risk in patients with T2D. The SCORE2 Asia-Pacific algorithms have been calibrated to estimate the 10-year risk of CVD in apparently healthy people in Asia and Oceania.¹⁰ However, SCORE2-Diabetes lacks a specific categorisation for individual countries in Asia, raising questions about its applicability as a reference for patients in these countries, including Thailand. Consequently, the development of a SCORE categorisation for each country in Asia is potentially important for patients. The authors propose that a high CV risk be defined as patients with T2D duration of ≥10 years with at least one of the following: established CVD; target organ damage; or three or more additional risk factors for CVD.

Treatment Targets in Diabetes and Established or High Risk Cardiovascular Disease

The authors state the treatment target of Thai T2D patients depends on their CV risk, as proposed in Table 2, using the ADA 2025 and ESC 2023 guidelines as guidance.^6,9

Glucagon-like Peptide-1 Receptor Agonists

Several studies of GLP-1 RAs have identified a variety of benefits, including glycaemic control, weight reduction and cardiorenal outcome improvements.

Meta-analyses of CV outcome trials (CVOTs), as shown in Table 3, demonstrated that the HR for major adverse CV events (MACEs) was lower than in patients receiving placebo, and GLP-1 RAs had about a 2.5-fold greater relative risk reduction for the MACE endpoint among Asians than Caucasians.^11,12 This suggests that Asian patients with T2D may achieve greater benefit from GLP-1 RAs compared to Caucasians. The possible explanations are earlier diabetes onset and lower BMI in Asians, so MACE or other CV risks driven by glycaemia-affected pathways are more pronounced in the Asian group.

In addition, an increase in glycaemic variability has been linked to adverse outcomes in CVD in an Asian population.¹³ GLP1-RAs have shown potential to reduce glycaemic variability while posing a low risk of hypoglycaemia.¹⁴ The expanding evidence illustrating the benefits of GLP-1 RAs among patients with T2D and with established or high-risk CVD supports the approval of GLP-1 RAs for use in Thailand, as shown in Table 4. However, the Thai population was included only in the outcome studies of PIONEER-6, EXSCEL, SUSTAIN-6 and Harmony.⁷

The 2023 ESC guidelines recommended GLP-1 RAs for patients with T2D and ASCVD to reduce CV events (class I, level A). However, GLP-1 RAs may be considered to lower the CV risk in patients with T2D who have a high to very high risk of CVD, (class IIb, level C). The authors did not fully agree that the subgroup analyses of CVOTs demonstrate a consistent reduction in MACE across a range of previous CV events. A GLP-1 RA is recommended following SGLT2Is for T2D patients with chronic kidney disease at eGFR >15 ml/min/1.73 m² to achieve adequate glycaemic control, owing to the low risk of hypoglycaemia and beneficial effects on weight, CV risk and albuminuria (class I, level A). Additionally, GLP-1 RAs should be considered in overweight or obese patients to reduce weight (class IIa, level B).

The authors suggest that early use of GLP-1 RAs is necessary and could also be focused on metabolic outcomes. The initiation of oral GLP-1 RAs in patients within 1 year of T2D diagnosis resulted in robust HbA_1c and body weight reductions as well as attainment of glycaemic targets, including near-normal HbA_1c.¹⁵

Practical and Safety Considerations

Patient history, prior diabetes treatments and choice of GLP-1 RAs are key considerations for the prescription of GLP-1 RAs. They can be determined through patient screening and healthcare professional consultation (Table 5).

The most common adverse effects associated with the use of GLP-1 RAs are gastrointestinal symptoms. Concerns about possible increased risks for suicidal thoughts, thyroid cancer and pancreatic cancer in patients taking GLP-1 RAs were discussed by the authors. Current evidence does not support a causal association between GLP-1 RAs and suicidal thoughts, thyroid cancer and pancreatic cancer.^16,17 Nonetheless, monitoring for these adverse events is still required.

Discussion

The macrovascular complications of T2D include CVD such as coronary artery disease, heart failure (HF) and peripheral artery disease, especially in patients whose diabetes is uncontrolled. Additionally, individuals with concomitant CV risk factors, such as advanced age, obesity, uncontrolled hypertension, dyslipidaemia or proteinuria, have a higher risk of CVD. Effective and early glycaemic control after diagnosis of T2D and control of other CV risk factors can prevent CV events.

GLP-1 RAs, whose mechanisms of action involve incretin hormones, exhibit several favourable effects, including weight reduction through regulating appetite by affecting brain areas and gastric emptying time and rate, stimulating insulin secretion without hypoglycaemia and have anti-inflammatory properties that contribute to reducing atherosclerosis.

Numerous large cardiovascular outcome trials of GLP-1 RAs have demonstrated reductions of MACE in patients with ASCVD. The SELECT trial demonstrated that a once-weekly 2.4 mg dose of semaglutide in overweight or obese patients with ASCVD but without T2D resulted in a 20% decrease in MACE.¹⁸ The STEP-HF with preserved ejection fraction trial results clearly indicated that semaglutide 2.4 mg once a week improved HF-related symptoms in patients with obesity and HF with preserved ejection fraction (HFpEF). Similarly, HFpEF trials in patients with T2D and obesity (including STEP HFpEF-DM) exhibited decreases in HF-related symptoms and physical limitations; tirzepatide reduced the risk of worsening HF and CV death by 38% in patients with obesity and HFpEF compared to placebo from the SUMMIT trial. Moreover, the findings showed tirzepatide also improved physical function.

In addition, several studies are exploring the effects of GLP-1 RAs on patients. The effect of once-weekly 1 mg doses of semaglutide on walking ability was investigated in patients with peripheral arterial disease and T2D in the recently completed STRIDE trial (NCT04560998). The CV effect of oral semaglutide for patients with T2D and ASCVD and/or chronic kidney disease (CKD) was investigated in the SOUL trial (NCT03914326). The SOUL trial achieved its primary objective by demonstrating a statistically significant and superior reduction in MACE of 14% with oral semaglutide compared to placebo.

The effects of oral semaglutide on MACE and other complications among patients with T2D but no history of MI or stroke are being investigated in the ASCEND PLUS trial (NCT05441267). Based on currently available data, no further assessment of CV outcomes of dulaglutide and liraglutide is being carried out. Two CVOTs of tirzepatide are being conducted: SURPASS-CVOT (NCT04255433), which is targeting individuals with T2D and a history of CVD; and SURMOUNT-MMO (NCT05556512), involving individuals who are overweight or obese; however, tirzepatide is unavailable in Thailand.

Further investigation into adherence and persistence in the lifelong use of GLP-1 RAs should be undertaken.

Patients with T2D commonly have CV risk factors. Healthcare professionals can choose between GLP-1 RAs and SGLT2Is in T2D patients with high CV risks. The primary approach to treatment emphasises optimising various risk factors and makes clinicians pivotal to the future adoption of GLP-1 RAs on a broader scale.

The obstacle to the future use of GLP-1 RAs lies in reimbursement, a pivotal concern for the healthcare systems in Asia. Healthcare models and treatment accessibility are diverse across the Asian region and unequal access, a focus on acute care and restricted availability of high-cost medications cause common gaps. There are three tax-funded healthcare schemes in Thailand: the Civil Servant Medical Benefits Scheme (CSMBS); the Social Security Scheme; and the Universal Coverage Scheme. More than 99% of Thai citizens are covered by one of these schemes.

GLP-1 RAs for T2D patients are fully covered only in CSMBS, while its use for individuals with obesity but not T2D is not covered by any scheme. GPs could play a significant role in expanding the use of GLP-1 RAs in early diagnosed T2D patients. However, they have restrictions on prescribing non-essential medications in accordance with medical regulations, and the high cost and limited accessibility of GLP-1 RAs may hinder their widespread use. A cost–benefit analysis based on real-world data on GLP-1 RA use in each Asian country, including Thailand, should be conducted; favourable results may lead to the drug’s inclusion in Thailand’s essential drug lists.

Additionally, there are tools, such as DIAL2 (DIAbetes Lifetime perspective model) and SCORE2-Diabetes, which could help physicians assess individual’s risk factors, including CV risks, among patients with T2D. However, the recently published SCORE2-Diabetes algorithm poses limitations owing to its non-categorisation of patients by Asian country, so the development of a CV risk score by nation would provide a link between the ESC guidelines and their recommendations for patients in each Asian country.⁹

The scope of this opinion paper is limited to GLP-1RA therapy and other antidiabetic agents with CV benefits are excluded. In addition, this expert meeting does not take real-world evidence of GLP-1RAs use into consideration.

Conclusion

An increase in CV awareness and CV risk screening is expected to lead to a greater adoption of medications with CV benefits, further reducing morbidity as well as mortality among patients with T2D. This expert group agreed with the recommended treatment targets for patients with T2D and established or high-risk CVD from the ADA and ESC guidelines.

This paper explicitly examines the use of GLP-1 RAs in the specific context of Asian patients in line with current international guidelines. There is a need for more specific guidelines tailored to the unique characteristics of different Asian populations. This is crucial to provide healthcare professionals with the information necessary to make decisions about GLP-1 RA therapy for their patients.

The aspects of reimbursement, affordability issues and limited accessibility of GLP-1 RAs mentioned in this paper will affect its practical implementation in clinical settings in Asia and, more specifically, Thailand.