FormalPara Key Summary Points

Some glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have demonstrated benefit for patients with type 2 diabetes (T2D) at risk of cardiovascular complications or with established cardiovascular disease.

Despite clinical guidelines recommendations to use GLP-1 RAs in these patients, the use of these medications is still suboptimal in Spain and worldwide.

The reasons for the limited use of GLP-1 RAs could be complex, and include clinical inertia, lack of awareness of the cardiovascular benefits by prescribing physicians, rejection of injectable medication by some patients, administrative issues, and higher costs compared with other drugs.

It is a matter of urgency to implement the recommendations from current clinical guidelines that encourage the use of GLP-1 RAs in patients with T2D and high cardiovascular risk.

Possible solutions include promoting physician education, a multidisciplinary approach to patient care, and increased awareness of the importance of treating comorbidities.

Introduction

Type 2 diabetes (T2D) is a chronic metabolic disease with a huge clinical and economic impact globally. In Spain, the total direct costs of treating T2D have been estimated at €10 billion yearly [1]. Therefore, the development of novel treatments and the optimisation of available resources are key to diabetes management. Currently, in addition to glucose-lowering efficacy, factors such as weight control and impact on comorbidities are usually considered in the evaluation of any new glucose-lowering therapies [2]. Also, the rise in costs and the effort to individualise care for T2D has promoted a multifactorial approach that aims to control risk factors for diabetes-related complications, and especially cardiovascular disease (CVD). Approximately 32% of patients with T2D develop CVD, and it is their leading cause of mortality [3]. A recent study of patients with T2D in the region of Catalonia, Spain, revealed that 93% of patients were at high or very high cardiovascular (CV) risk [4]. For these reasons, and given the burden of CVD and the elevated costs of care, primary and secondary prevention of CVD among patients with T2D is a priority [5].

The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs with potent glucose-lowering effects [6]. Clinical studies have demonstrated that GLP-1 RAs can lower glycated haemoglobin (HbA1c) by more than 1.0% from baseline values with a reduced risk of hypoglycaemia compared with sulfonylurea and insulin [7]. In addition, some GLP-1 RAs have beneficial effects in other conditions frequently associated with diabetes, such as overweight and obesity, hypertension, hyperlipidaemia, and most importantly atherosclerotic CVD [6, 8, 9]. The accumulated evidence shows that some GLP-1 RAs can reduce the occurrence of major adverse CV events, CV mortality, and all-cause mortality risk, without significant known safety concerns [8, 10, 11]. The basis for the CVD effects of GLP-1 RAs is not fully understood, but there is strong evidence supporting clinically relevant anti-inflammatory and antioxidant effects of these drugs [12]. Although GLP-1 RAs are generally recommended for secondary prevention in patients with T2D and established CVD or at high CV risk, for dulaglutide an added benefit in early primary prevention has been demonstrated [13, 14].

Current guidelines suggest use of GLP-1 RAs with proven CV benefit (liraglutide, subcutaneously administered semaglutide and dulaglutide) in patients at high risk or with established atherosclerotic CVD, regardless of glycaemic control, with lifestyle modification and independent of the use of metformin [7, 13, 15, 16]. Apart from the CVD benefit, other guidelines also focus on weight reduction and restrict their use exclusively to patients with high body mass index (BMI) [17]. Yet other guidelines offer a combined approach and advise use of GLP-1 RAs in patients with CVD and/or high BMI [2, 18,19,20]. Guidelines in Spain underscore that the adequate treatment of T2D requires a simultaneous approach to HbA1c, overweight/obesity, and other CV risk factors such as hypertension, dyslipidaemia or smoking, and highlight that the presence of CVD is a determinant factor for treatment selection [2, 21, 22].

Given the complexity of possible treatment pathways, it was of interest to analyse the available evidence from real-world clinical practice in Spain with respect to GLP-1 RA use. Therefore, we reviewed all observational studies with data on this topic published from 2016 to 2021. A second objective was to assess the extent to which the use of GLP-1 RAs is in line with guideline recommendations, to obtain information on possible reasons for mismatches, and to evaluate possible strategies or recommendations to bridge the gap between guidelines and clinical practice regarding use of GLP-1 RA. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

How Are GLP-1 RAs Being Used in Spain?

GLP-1 RAs are infrequently prescribed among patients with diabetes worldwide. In the USA, it has been estimated that approximately only 1–5% of people with diabetes are prescribed GLP-1 RAs, despite the potential benefits of these drugs in patients with diabetes and CVD [23,24,25,26,27]. A database study in Spain showed that only 3.2% of patients with T2D started treatment with a GLP-1 RA (dulaglutide, exenatide, liraglutide) [28]. A study from Catalonia, in the northeast of Spain, showed that, despite a prevalence of CVD of 23.2% in the population with T2D, only 1.4% were prescribed GLP-1 RAs [27].

Several studies carried out in Spain provide a description of the real-world demographic and clinical characteristics of the population that initiate GLP-1 RA treatments (Table 1). The cross-sectional CHADIG study was the first to assess the characteristics of patients initiating GLP-1 RAs, concluding that these drugs were usually combined with oral glucose-lowering drugs approximately a decade after T2D diagnosis, and that patients were relatively young, with poor glycaemic control, and a high BMI [29]. More recent studies agree that patients starting GLP-1 RAs usually have a mean age of approximately 60 years, a BMI > 35 kg/m2 and HbA1c > 8.1% [28, 30, 31]. Additionally, these studies showed that the time since diagnosis of diabetes to initiation of GLP-1 RAs was greater than 9 years, reflecting long-standing and probably poorly controlled diabetes [28, 32]. This is also reflected in the fact that GLP-1 RAs are often used in combination with other glucose-lowering medication such as metformin, insulin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and sulfonylureas [28], suggesting that they are used in later phases of diabetes and not mainly after metformin, as suggested by guidelines [2, 18,19,20].

Table 1 Studies with data on real-world clinical use of GLP-1 RAs in Spain (2016–2021)
Full size table

Real-world studies show that most patients initiating GLP-1 RAs present with one or more comorbidities. Interestingly, only 21.8% of the patients presented with established CVD (macrovascular) when initiating GLP-1 RAs [28], suggesting that the presence of CVD is not a main criterion for their use. In a study of patients in the region of Catalonia, 33.6% presented with CVD [30]. This is within the range of the prevalence of CVD in the general T2D population, which ranges from 6.9% to 40.8% [5]. In addition, most patients have high or very high CV risk [4].

A recent survey on the use of glucose-lowering medication in primary care in Spain (CONTROVERTI2) showed that the use of GLP-1 RAs is associated with patients with T2D and obesity, while patients with established CVD are preferentially treated with SGLT2 inhibitors [33]. However, a national level study of elderly patients with T2D admitted to hospital and at very high CV risk concluded that most were not being treated with these drugs [34].

In summary, the data from recent years in Spain show that GLP-1 RAs are mainly used in patients with high BMI (> 35 kg/m2), HbA1c levels above 8%, with comorbidities and a long history of diabetes, but not especially in patients with established atherosclerotic CVD or high CV risk. This suggests that in Spain, there is a gap between the guidelines that propose the use of GLP-1 RAs in patients with established atherosclerotic CVD/high CV risk and real-world clinical practice, which shows that they are used in patients with T2D and obesity with long-standing and poorly controlled diabetes.

These results agree with another retrospective study in Italy showing that patients initiating GLP-1 RAs presented with an HbA1c of 8.3% and a BMI of 34 kg/m2 at baseline. In addition, the data showed there were significant increases in the last 10 years in age at baseline, diabetes duration and CVD for these patients [35].

Potential Reasons That Limit the Use of GLP-1 RAs Based on Their CV Benefit

Characteristics of the Spanish National Health System

Despite the evidence of CV benefit with the use of GLP-1 RAs included in Spanish guidelines, this benefit was not considered in reimbursement decisions, which took place before the publication of the landmark studies showing CV benefit of GLP-1 RAs. Currently in Spain, a high BMI (≥ 30 kg/m2) is an essential factor for reimbursement. The reason for recommending the use of GLP-1 RAs to patients with high BMI was based on models developed by the National Institute for Health and Care Excellence in the UK, for some specific GLP-1 RAs (exenatide and liraglutide) that were then generalised for the drug class [36]. It has been argued that restricting GLP-1 RA therapy to patients with BMI > 35 kg/m2 based exclusively on weight loss may be counterproductive if glycemic efficacy is not maintained [36], and it could set unrealistic goals for both prescribing physicians and patients [32]. Although weight loss should be an objective in patients with obesity and diabetes, it should not be a determinant for the prescription of GLP-1 RAs. The benefits of glucose control and reduction of CV risk with GLP-1 RAs have also been proven in non-obese patients with T2D [16, 21, 37]. However, although the limitation by the Spanish National Health Service could affect the use of GLP-1 RAs, it may not be the major reason for the majority of patients, as other countries without the BMI limitation have similar prescription rates as Spain [26, 38, 39].

Clinical Inertia

It is possible that lack of physician familiarity with GLP-1 RAs, or clinical inertia, are partly responsible for the reduced use of GLP-1 RAs. Therapeutic inertia has been shown to be a significant barrier to glycaemic control, ultimately contributing to long-term complications in high-risk patients [40, 41]. Currently, the focus of diabetes treatment has shifted from strict glycaemic control to a more comprehensive approach that considers prevention or control of CVD, kidney disease or other diabetes complications [13, 42]. Accordingly, a recent survey suggested that one of the most influential clinical factors in the choice of glucose-lowering treatment in Spain is the presence of CVD (the other being high HbA1c) [33]. The current guidelines recommend SGLT2 inhibitors or GLP-1 RAs for the management of patients with T2D and established atherosclerotic CVD, while SGLT2 inhibitors are preferred for patients at risk of heart failure [2]. However, a Delphi study found that, although SGLT2 inhibitors are the treatment of choice in patients with T2D and heart failure or uncontrolled hypertension, no consensus was reached regarding the preferential use of SGLT2 inhibitors or GLP-1 RAs in patients with established CVD. This study also revealed that management of patients with T2D in primary or secondary CV prevention is highly heterogeneous in real-world clinical practice in Spain [43]. Another recent Delphi study also showed that the presence of CVD or high CV risk was a more influential factor for the choice of glucose-lowering treatment than baseline HbA1c levels [44]. Although the Delphi surveys support a treatment choice based also on CV criteria, it seems that this opinion is not being reflected in the use of GLP-1 RAs in real practice.

Injectable Medication

To date, the GLP-1 RAs that have shown CV benefit have subcutaneous administration and it is possible that patients reject the concept of injectable therapy when they first encounter it. GLP-1 RAs are recommended before insulin initiation as the first injectable therapy [13, 16]. However, insulin is still often the first injectable therapy in Spanish patients with T2D, suggesting that the route of administration would not be a strong barrier [28]. Also, weekly administration is available for GLP-1 RAs, which may be preferable to daily insulin and improve adherence to treatment [45, 46]. Studies have shown that the type of injection device and needle size are important attributes driving patient preferences for specific GLP-1 RAs. Understanding these preferences could help improve patient adherence and clinical outcomes [47].

Costs of GLP-1 RA Treatment

While older oral glucose-lowering medications (i.e. metformin, biguanides, sulfonylureas, glinides, thiazolidinediones or α-glucosidase inhibitors) are relatively inexpensive, the newest agents approved for diabetes (i.e. GLP-1 RAs, dipeptidyl peptidase 4 inhibitors and SGLT2 inhibitors) are comparatively more costly. However, the largest part of the cost of diabetes management is consultations, hospitalisations and the treatment of diabetes-related complications, especially if CVD develops [1, 5]. Cost–utility analyses of dulaglutide and other GLP-1 RAs have shown them to be a cost-effective treatment option as add-on therapy to metformin or directly compared to insulin in several countries [48,49,50]. Several comparative pharmacoeconomic analyses have been recently carried out in Spain regarding GLP-1 RAs [51,52,53,54,55,56].

Important differences and variabilities in the uptake of new glucose-lowering medicines in European countries have been observed. The high cost gap between old and new antidiabetic medicines and their financial burdens could affect market uptake and consequently patient access [57]. However, there are no studies showing that costs of GLP-1 RA treatment could strongly influence prescription of this group of drugs [57].

Other Reasons

As is the case with other chronic diseases, most T2D treatments often have low adherence and persistence. In this regard, observational studies in Spain also have shown that, even after a first prescription of GLP-1 RAs, adherence to treatment is low and discontinuation is high [28, 32], with a mean GLP-1 RA treatment duration of 1 year [28]. It was speculated that early discontinuation rates could be due to gastrointestinal side effects that commonly appear at the beginning of GLP-1 RA treatment [28]. However, a study showed that gastrointestinal adverse events were self‐reported by a low proportion of patients (14.96%), most of them by the first follow‐up visit [32].

Some guidelines recommend discontinuation if no beneficial response is observed within 6 months of therapy initiation. Efficacy has been defined as a combined reduction of at least 1.0% in HbA1c levels and 3% in initial weight [17]. Similar advice is found in regional health services in Spain [30, 32]. In Spain, the proportion of patients who discontinued treatment in an observational study largely matched with the proportion of patients not meeting the efficacy requirements as per the proposed definition (37.07%) [32]. It has been argued that requiring more than a 1% HbA1c reduction with GLP-1 RA treatment lacks justification because the HbA1c reduction is closely associated with baseline HbA1c [36]. It has been proposed that treatment withdrawal should be judged from a patient-centred approach, as about 80% of the patients who potentially could benefit from these treatments could not reach those targets [31, 36]. Also, these criteria for discontinuation were proposed prior to studies demonstrating CV benefit for many patients and should be revised in light of the new evidence.

Towards a New Focus of the Therapeutic Role of GLP-1 RAs in Spain

As described, the limitations in the implementation of therapies involving GLP-1 RAs could have patient, clinician and system-level origins. The existence of major gaps in the implementation of effective, evidence-driven therapies in patients with T2D and CVD has been highlighted in other countries [25, 26]. Adoption of these therapies could save lives by decreasing major atherosclerotic CV events and disease progression [26]. Recent reports have highlighted the urgency of implementing guidelines to ensure that patients with T2D and high cardiorenal risk benefit from GLP­1 RAs and SGLT2 inhibitors [25, 58].

A multidisciplinary approach to the treatment of diabetes could improve the treatment of patients with cardiorenal risk [58]. Both the American Diabetes Association/European Association for the Study of Diabetes consensus report and the European Society of Cardiology guidelines urge cardiologists, endocrinologists, nephrologists, primary care providers and pharmacists to implement the use of GLP-1 RAs and SGLT2 inhibitors in clinical practice [13, 59]. For patients at risk, treatment at early stages of the disease is beneficial and should be encouraged [60]. As diabetes therapies are constantly improving, continued medical education of healthcare providers on their relative benefits should be a priority to overcome clinical inertia. Management of diabetes should change from a ‘glucocentric’ view to one in which the individual risks of the patient are taken into consideration. Likewise, a more detailed evaluation of the clinical histories of patients and their evolution could help improve personalised treatments and adapt them to emerging comorbidities.

The treatment of T2D requires long-term commitments and substantial changes in lifestyle, for which patient involvement is essential. Patient-centred approaches, which emphasise patient choice and shared decision-making in diabetes management, have been a focus of disease management [7]. In this regard, patients will need to be educated on the benefits of adherence to medication, and in the need to control comorbidities. Bridging these gaps will require the concerted action of patient associations, healthcare providers, regulators, professional societies and payers.