The diabetic patient between sustainability and effectiveness of new treatments

Abstract

Objectives

The increased issuance and distribution of new agents for type 2 diabetes mellitus, due to relaxed prescribing rules, has resulted not only in a greater proximity of treatments to the patient, as envisioned by post-Covidio 19 European policies, but also in an unexpected increase in healthcare spending.

Methods

An analysis of a database called “Health Card” was performed in order to evaluate all prescriptions for the new classes of medications used for type 2 diabetes.

Results

New legislation called “note 100” was introduced in early 2022, outlining the eligibility of certain categories of drugs used for the treatment of type 2 diabetes mellitus for direct prescription by primary care physicians in Italy. This investigation therefore delves into an examination of the prescribing patterns related to these drugs, contrasting the year 2021, prior to the implementation of Note 100, with the year 2022, following the incorporation of the new legislation. The result resulted in an exponential increase in prescriptions and consumption (+ 38%) and increased healthcare spending of more than three million euros for these drug categories.

Conclusion

This analysis highlights how regulation on the one hand leads to facilitating prescribing to meet a population need that is not fully satisfied, but on the other hand leads to increased prescribing and increased health care expenditures that may likely mask phenomena of prescribing inappropriateness.

Introduction

The care of people affected by diabetes includes more than just prescribing medications. It involves the promotion of a healthy lifestyle (appropriate diet, regular physical activity, avoidance of smoking), the education on at-home self-management, the conduction of periodic clinical assessments, and the prevention of acute and chronic complications. The evaluation of chronic complications deriving from type 2 diabetes should be undertaken at least once annually [1]. It is also crucial to integrate patients into a comprehensive diagnostic, therapeutic, and care pathway that collaboratively includes diabetology and general medicine services. To mitigate the risk of acute and chronic complications, it is essential for people affected by diabetes to have blood glucose and glycated hemoglobin within levels suitable for their specific clinical situation [2]. Glycated hemoglobin (HbA1c) stands as the main metric for the evaluation of glycemic control, as it serves as the benchmark used in clinical trials to substantiate treatment benefits. Recent systematic analysis utilizing network meta-analysis have examined the efficacy of glucagon-like peptide 1 (GLP1) receptor agonists, dipeptidil-peptidasi IV (DPP4) inhibitors, and sodium/glucose cotransporter 2 (SGLT2) inhibitors as supplementary treatments to metformin for lowering HbA1c in adult patients with type 2 diabetes mellitus (DM). Generally, long-acting GLP1 receptor agonists exhibited a more consistent reduction compared to the other alternatives [3]. An essential aspect concerns to assessing the tolerability of diverse medications. Each drug class has contraindications or usage precautions that require careful consideration before prescribing. Furthermore, it is imperative to recognize that certain patient demographics such as the elderly (> 75 years) have limited efficacy and safety data available. Eventually, since there is an equivalent benefit/risk ratio for the individual patient, the choice of the most economically feasible treatment option should be a crucial factor. Metformin emerged as the pioneer hypoglycemic drug to demonstrate efficacy in reducing cardiovascular-related mortality risk among overweight or obese patients, prompting its endorsement as a first-line treatment for all individuals with type 2 diabetes. In investigations spotlighting the good impact of other drug categories in reducing cardiovascular event risk for patients with or without prior incidents, these agents have been added to existing therapies, frequently featuring metformin [4]. Type 2 DM has deleterious effects on various organ systems and therefore, appropriate management of the disease is crucial [5]. Therefore, diabetes treatment require different drug choices in different accompanying clinical conditions [6] and an effective management of the disease may improve diabetic outcomes [7]. Several randomized clinical trials have evidenced the substantial advantages of SGLT2 inhibitors and GLP1 receptor agonists concerning the reduction of significant cardiovascular incidents and cardiovascular-related mortality in patients with established cardiovascular disturbs or multiple risk factors [8–10]. The clinical advantages resulting from the utilization of SGLT2 inhibitors and GLP1 receptor agonists seem to transcend initial glycated hemoglobin levels, with more benefits in individuals already affected by cardiovascular disease. Several proofs underscore the high impact of SGLT2 inhibitors and, to a lesser extent, GLP1 receptor agonists on the progression of kidney impairment [10–12]. Notably, specific investigations focusing on canagliflozin and dapagliflozin have exhibited benefits primarily centered around decelerating the advancement of renal deterioration among patients with macroalbuminuria or those initially experiencing reduced glomerular filtration rate (GFR) [13, 14].

Conversely, focusing on DPP4 inhibitors, outcomes from randomized clinical trials do not indicate any cardiovascular advantages and do not establish a protective role in reducing the progression of renal diseases [15]. Consequently, DPP4 inhibitors should be considered secondary options for individuals affecting by chronic kidney disease or cardiovascular disorders. Nonetheless, these drugs have been recognized to have a favorable tolerability profile and handling administration.

The Italian Medicines Agency (AIFA), through Determination No. 19 dated January 25, 2022, introduced AIFA Note 100 to regulate the prescription of SGLT-2 inhibitors, GLP-1 receptor antagonists, DPP4 inhibitors, and their combinations for the treatment of type 2 diabetes mellitus under the National Health Service (NHS). With the implementation of Note 100, both the initial prescription (commencement of treatment) and subsequent renewals or adjustments of prescriptions for the medications outlined in the Note can be formulated by either a specialist physician affiliated with public healthcare facilities specializing in diabetes treatment or a general practitioner (GP). The introduction of Note 100 makes obsolete all therapeutic plans (PTs) filled out exclusively by specialist “diabetologists”. To complete a prescription, the physician need to complete the accompanying prescription form included in the Note. For treatment initiation, an evaluation and initial prescription form must be completed. It is valid for a maximum of 6 months. In instances of prescription renewal (for patients already on treatment with one of the drugs specified in the Note), a prescription renewal form is to be filled out, with a maximum validity period of 12 months. While presently available in paper format (editable PDF), plans are underway to transition to a digital format for the prescription form. A pivotal criterion outlined in the Note stipulates that prescribing medications falling within the three categories enumerated in Note 100 is possible when a therapeutic regimen including metformin (either alone or in combination) fails to achieve or sustain the target HbA1c level [16]. Note 100 establishes specific criteria for the eligibility of reimbursement under the NHS and outlines preferred indications for the use of the three drug categories based on patient characteristics, in particular in the presence of cardiovascular disease and chronic kidney disease. However, prescriptions charged to the NHS must consistently adhere to the guidelines, contraindications, and usage precautions specified in the individual drug data sheets. Even with the introduction of Note 100, the responsibility for prescribing pre-formulated or customized combinations of drugs mentioned in the Note (such as combining an SGLT2 inhibitor with a DPP4 inhibitor or an SGLT2 inhibitor with a GLP1 receptor agonist) remains under the diabetologist expertise. In such instances, the general practitioner can prescribe within the validity period of the prescription form provided by the diabetologist. For the purpose of NHS reimbursement, the prescription of drugs listed in Note 100 is mandatory only for the treatment of type 2 diabetes. The prescription serves as the documentation that facilitates the management of drug therapy for people with type 2 diabetes mellitus as outlined in Note 100. As the Note transitions into a computerized format, physicians will be able to directly access a computerized system known as the “TS Health Card” to gather information about patient’s treatment regimen. During the ongoing temporary paper-based phase, the prescribing physician must provide the patient with at least one copy of the prescription card (to be shown to the family doctor if the prescriber is a different physician). The prescriber is also required to retain a copy of the prescription, whether in paper or PDF format [17].

Due to the wide range of therapeutic classes available for managing Type 2 diabetes mellitus, the new regulations in Italy aim to amplify the clinical responsibilities of general practitioners. This shift aims to empower them to carefully evaluate and select the most suitable treatment for their patients dealing with one of the most widespread chronic conditions. Nonetheless, the objective of this study is to underscore the dual impact of these regulations. On one side, this approach streamlines the prescription process for certain categories of medications with higher costs. This broadens the spectrum of therapeutic options accessible to individuals, thus enhancing their choices for managing their health. Conversely, this initiative exerts a substantial influence on healthcare expenditure, potentially contributing to an escalation in the utilization of pricier drug categories. As a result, whereas these regulations enable improved patient access to diverse treatment choices, they concurrently can induce a significant financial strain on healthcare systems due to the heightened usage of higher-cost pharmaceutical categories.

Guidance for prescriptibility under the NHS

Guidelines regarding the proper prescription of antidiabetic drugs highlight the following [18]:

• A.Lifestyle modification (medical nutrition therapy-diet, physical activity, abstention from smoking) represents the first step in the treatment of diabetes, at any age and in any clinical condition, as an intervention indispensable in the overall therapeutic strategy. The magnitude of benefit of such an intervention is at least superimposable to the effect of an initial treatment pharmacological treatment and is free of adverse events.
• B.
  If lifestyle modification is not sufficient (after at least 3 months) compared with the predetermined individual HbA1c goal (see point C), the drug of first choice for the treatment of type 2 diabetes is metformin, unless contraindicated or intolerant.

  • The gastrointestinal tolerability of metformin can be improved by gradual titration in the first weeks of treatment and by postprandial intake (< 5% of patients discontinue due to intolerance).
  • In the event that metformin is contraindicated or not tolerated, they can be used as monotherapy with all other drugs. The choice of the drug to used should take into account the patient’s characteristics (risk factors and comorbidities) and the indications and contraindications in the data sheet.

• III.Although individualizable, the goal of glycated hemoglobin (HbA1c) in the patient treated with drugs not associated with hypoglycemia is generally below below 53 mmol/mol (7.0%), a value that can reduce the incidence and progression of micro- and macrovascular complications and mortality. A more intensive control with values below 48 mmol/mol (6.5%) can be considered in selected cases based on clinical judgment. In the case of the use of medications associated with hypoglycemia, it is, however, appropriate to maintain HbA1c at relatively higher levels, up to 58 mmol/mol (7.5%).

• IV.
  If a treatment regimen containing metformin (alone or combined with other drugs) is not sufficient to achieve/maintain of the established individual HbA1c goal or in the event that it is considered necessary to replace one of the associated treatments even in the presence of HbA1c values within the individual targets, one should consider association and/or replacement, specifically with:

  • An SGLT2* inhibitor or a GLP1* receptor agonist (both when not contraindicated and well tolerated) should be considered preferentially in the following clinical scenarios:

    1. Patient in secondary CV prevention;
    2. Patient in primary CV prevention who is at high CV risk;
  • An SGLT2* inhibitor (when not contraindicated and well tolerated) should preferentially be considered in the following clinical scenarios:

    • 3.
      Patient with chronic kidney disease (presence of VFG < 60 mL/min and/or micro or macro albuminuria)**;
    • 4.
      Patient with heart failure.
      (* For active ingredients for which there is a demonstration of a benefit clinical benefit on these parameters
      ** in compliance with the RCPs of the individual drugs).
      In patients 1, 2, 3 and 4, DPP4 inhibitors should be considered especially when recommended drugs are contraindicated/ not tolerated (e.g., VFG < 30 mL/min or elderly subject).
  • In the patient without chronic kidney disease, without cardiovascular disease and not at high risk for cardiovascular disease, there is currently not available sufficient evidence to recommend the use of a specific class of drugs than the others covered in the Note. In such patients, the therapeutic choice must take into account several factors such as the characteristics individual of the subject, the tolerability profile of the drug, the extent of reduction in HbA1c that is intended to be achieved or the effect on body weight.
    Secondary CV prevention is defined as the presence or positive history of:

    • cardiovascular disease: ischemic heart disease, previous IMA, bypass coronary artery bypass, angioplasty, coronary revascularization procedure;
    • cerebrovascular disease: previous stroke or TIA, revascularization carotid artery;
    • symptomatic peripheral arterial disease.
  • High CV risk, in the patient without overt or anamnestic, is defined as: presence of documented atherosclerotic vascular damage (e.g., disease multivessel coronary artery disease or carotid stenosis > 50%); presence of damage in a target organ; presence of at least three CV risk factors (among age > 50 years, hypertension blood pressure, dyslipidemia, obesity, cigarette smoking).
  • Chronic kidney disease is defined as: VFG less than 60 mL/min and/or presence of albuminuria (micro and macro).
• V.SGLT2 inhibitors, GLP1 receptor agonists and inhibitors of DPP4 can be combined with insulin therapy, which is a therapeutic option in all stages of type 2 diabetes mellitus and represents, in addition, the option of choice for the treatment of glycemic emergence, according to the authorized indications and as reported in item D above.
• VI.Associations, extemporaneous or preconstituted, between drugs covered by the Note remain of specialist relevance as part of a more complex that will have to be carried out taking into account the characteristics of individual patients and the general considerations given in the Note.

Methods

A comprehensive examination of prescription data pertaining to the pharmaceuticals governed by the new Italian regulations for type 2 diabetes mellitus has been conducted at Napoli 3 Sud. Leveraging a computerized system that records all prescriptions dispensed within the region, an in-depth assessment has been performed on the dispensing details of the medications encompassed by Note 100. This has been achieved by calculating the Defined Daily Dose (DDD). The DDD stands as the average daily quantity of a drug, tailored for its primary indication, for use in an adult patient. It serves as an internationally standardized benchmark, allowing for the comparison of treatment regimens utilizing different packaging sizes and similar therapeutic categories. This metric holds particular advantages over mere “number of pieces” metrics as it provides a more comprehensive evaluation of the prescribed drug quantity, irrespective of packaging format. The DDD calculations have been carried out in relation to territorial consumption, considering the average daily dose per 1,000 residents, adjusted for the population occupancy rate. The forthcoming computerization of the treatment plans (PTs) through the “TS Health Card” system will undoubtedly foster the cross-referencing of data, enabling more precise analysis with statistical insights. The ongoing analysis seeks to determine, without the use of specialized statistical techniques, the variations in expenditure and consumption patterns of antidiabetic medications both prior to and subsequent to the enactment of Note 100.

Results

The population encompassed by the administrative jurisdiction of Napoli 3 SUD exceeds one million individuals, with the combined use of the mentioned pharmaceutical substances increasing fourfold during the two-year period after the issuance of Note 100. Following this, a thorough examination is carried out, utilizing the metric of defined daily doses (DDDs), with the intention of confirming the significant rise in the usage of these therapeutic agents (Table 1). Simultaneously, a thorough analysis is conducted to clarify the increase in financial expenses, occurring within a mere twelve-month timeframe after the introduction of the current national regulations. This evaluative endeavor is executed within an extensive cohort, characterized by the population of an Italian Administrative Health Authority (Asl) located to the south of Naples, thus providing a comprehensive view.

Table 1.

DDDs of type 2 antidiabetic drugs regarding Note 100 consumed in the 2021 and 2022 at Asl Napoli 3 Sud 

Key elements of the analysis	N
Population Asl Naples 3 year 2021	1,044,024
DDD year 2021	829,223
DDD year 2022	2,325,741

The analysis performed in each instance aims to conduct a pharmaco-utilization investigation: the alteration in expenses during the two reference periods is solely attributable to the escalated utilization of specific medications, as outlined in Note 100, which maintained an unaltered price in both 2021 and 2022. In 2021, as illustrated in Table 2, the outlay linked to drugs for type 2 diabetes, affected by Note 100, totaled €6,304,626.81, with €1,654,231.25 (26.24%) allocated to DPP4 inhibitors, €1,235,124.20 (19.59%) to SGLT2 co-transporter inhibitors, and €3,415,271.36 (54.17%) to GLP1 receptor analogs. The latter class of medications is the most extensively prescribed for addressing type 2 diabetes, and its usage has substantially risen owing to its effectiveness and synergy with metformin. In the year 2022, prescriptions for these medications are anticipated to increase, resulting in an expense surge to €10,177,698.25, while the prescription distribution across various drug classes remains unaltered. Among these, a sum of €1,856,123.49 (18.24%) corresponds to DPP4 inhibitors, €2,536,246.33 (24.92%) pertains to SGLT2 co-transporter inhibitors, and €5,785,328.43 (56.84%) represents the expenditure attributed to GLP1 receptor analogs.

Table 2.

Type 2 antidiabetic drug dispensing data regarding Note 100 in the 2021 and 2022

Medications	2021	(%) 2021	2022	(%) 2022
Inhibitors DPP4	1,654,231.25 €	26.24%	1,856,123.49 €	18.24%
SGLT2 Cotransporter inhibitors	1,235,124.20 €	19.59%	2,536,246.33 €	24.92%
GLP1 Receptor analogs	3,415,271.36 €	54.17%	5,785,328.43 €	56.84%
Total	6,304,626.81 €		10,177,698.25 €

Table 3 demonstrates that in the two years under examination, there exists an augmentation in the overall expenditure concerning these medications, amounting to €3,873,071.44. Within this increment, €201,892.24 (+ 10.88%) pertains to DPP4 inhibitors, €1,301,122.13 (+ 51.30%) constitutes the expense attributed to the distribution of SGLT2 co-transporter inhibitors, and €2,370,057.07 (+ 40.97%) signifies the escalated expenditure resulting from the heightened prescription of GLP1 receptor analog drugs.

Table 3.

Increase in spending following the introduction of Note 100 comparing the 2021 and 2022

Medications	Δ (2022 − 2021)	Δ (%)
Inhibitors DPP4	201,892.24 €	+ 10.88%
SGLT2 Cotransporter inhibitors	1,301,122.13 €	+ 51.30%
GLP1 Receptor analogs	2,370,057.07 €	+ 40.97%
Total	3,873,071.44 €	+ 38.05%

The prescribing pattern for DPP4 inhibitors remained relatively stable over the two-year comparison (+ 10.88%). In contrast, SGLT2 co-transporter inhibitors and GLP1 receptor analogs witnessed substantial spikes in prescription rates, with increases of + 51.30% and + 40.97%, respectively. These medications represent the latest advancements and consequently result in the most substantial expenses, particularly when considering that metformin, which incurs a now negligible cost, still retains its status as the gold standard for type 2 antidiabetic therapy.

Discussion

Recent European regulations emphasize the importance of facilitating prescribing for chronic therapies, aiming to enhance patient engagement, adherence, and treatment efficacy. Italy has empowered general practitioners to prescribe treatments that have become standard in clinical practice, including new drugs for type 2 diabetes. The impact of the pandemic has highlighted the challenges faced by chronic patients due to limited interaction with specialist physicians for follow-up visits and treatment adjustments [19, 20]. This situation has led to decreased adherence and a significant reduction in reporting adverse events to the Pharmacovigilance system [21–23]. However, this analysis shows that the increased prescribing of higher-cost therapies by general practitioners has resulted in a substantial surge in healthcare expenditures for newer type 2 antidiabetic drugs. Comparing periods before and after the introduction of Note 100, a sharp increase of over 1.5 million euros has been observed in the two years. Although GPs have surely met an unsatisfied therapeutic need from patients who were eligible to the treament before the introduction of Note 100, this increase may suggest that a large number of patients may have been prescribed therapies that go beyond their actual treatment needs. As a result, increase in consumption and spending leads to focus on a potential inappropriateness of prescriptions, generating a significant cost escalation. While acknowledging the challenges posed by the pandemic and the unmet needs it generated, the outcomes of this analysis indicate a spending and consumption growth. Regardless, it is noteworthy that specialists have a broader understanding of the disease and the available therapeutic options, which can lead to more informed and suitable treatment choices. This observation could be confirmed through further studies involving statistical analyses over more extensive timeframes, post the implementation of the new regulations. This analysis serves as a cautionary alert to local healthcare administrators and decision-makers regarding the potential consequences of the policy to bring high-cost therapies closer to patients. If the trend of inappropriateness holds true, it might prompt a reevaluation of decisions to mitigate negative effects. Literature from other countries reveals a different approach, prioritizing the expansion of public facilities and specialist involvement to ensure accessibility to patients [24–29]. These countries have developed comprehensive and widespread public health systems that offer effective, appropriate and affordable medicines. Italy has a national health service that offers complete health care to the citizen, therefore the objective could be set to further strengthen the public health infrastructure, improving access for citizens and promoting the prudent use of available resources.

This transformative initiative suggests the concurrent establishment of new regulations within the framework of the NHS. In particular, the strengthening of the Coordination Areas of the Territorial Pharmacies represents a valid solution to halt the escalation of the increase in healthcare expenditure. The integration of computerized prescription surveillance, informative precinct assemblies delineating contemporary therapeutic precepts, coupled with unceasing interdisciplinary dialogues among healthcare constituents, emerges as a formidable arsenal to propagate apposite prescription practices. This concerted endeavor is hinged on the scaffolding of a novel healthcare governance paradigm, grounded on the bedrock of value-centric care.

The increase in the prescriptions and dispensing of these medicines suggests that the introduction of new therapeutic strategies that are more accessible for chronic patients could increase their use, consequently simultaneously increasing health care expenditure. It is crucial that all regional or local governments ensure unrestricted access to effective therapies for patients affected by diabetes, with the aim to improve healthcare cost containment.

Limitations of the study

To streamline the analysis, we have excluded considerations of drug category associations that, in certain instances, are subject to distinct regulations, thereby excluding them from Note 100. We’ve also made simplifications that we deem negligible and believe they do not undermine the validity of the analysis or its conclusions:

1. The scope of this analysis covers treatments that are already extensively utilized in routine clinical practice. Therefore, whether analyzing treatment-naive or previously treated patients doesn’t alter the outcomes. The surge in spending is substantial enough to undoubtedly stem from heightened drug prescription, and this holds true regardless of patient status.

2. The impact of introducing Note 100 results in an increased prescription of type 2 antidiabetic drugs, whether instigated by general practitioners (which is more logical) or specialists. This heightened prescription trend is consistent and remains unchanged, regardless of the prescriber.

In addition, there are two positive factors that serve to temper the potential margin of error in this analysis:

1. We have omitted considerations of drug class associations, some of which would fall within the ambit of Note 100. This omission is due to the complexities involved in selecting Anatomical Therapeutic Chemical Classification (ATC) codes, which, in any case, wouldn’t substantially alter the analysis outcome compared to considering only non-associated drugs.

2. The analysis focuses on the initial half of the year immediately following the Note 100 implementation. During this period, the prescription behavior of general practitioners may not have yet reached full capacity, introducing an element of conservatism in the analysis.

These simplifications and considerations aim to maintain the integrity of the analysis, despite certain nuances, and seek to ensure that the results hold relevance in capturing the essence of the observed trends.

Recommendations of major national and international guidelines

The guidance below is useful for further study of the role of the different drug classes. It should be noted, however, that AIFA Note 100 takes into necessarily takes into account, in addition to the general recommendations emerging from the guidelines, as well as the indications currently authorized by the EMA for individual drugs.

ESC/EASD 2019. The most recent guidelines [30] from the European ESC/EASD societies. (European Society of Cardiology and European Association for the Study of Diabetes) differentiate two types of patients with type 2 diabetes: patients with established cardiovascular disease (ASCVD, atherosclerotic cardiovascular disease) or at high/very high risk (due to organ damage or multiple risk factors) of cardiovascular disease and moderate-risk patients without disease or other cardiovascular risk factors. In the patient with ASCVD or at high/very high risk high is recommended treatment with an SGLT2 inhibitor or a GLP1 receptor agonist in each case, whether the patient is a patient not yet treated with antidiabetic drugs, or whether the patient is already being treated with metformin, and regardless of do HbA1c levels. In the patient at moderate cardiovascular risk, metformin remains the treatment of first choice to which should be added, in case of failure of the HbA1c target, a second drug of choice among SGLT2 inhibitors, GLP1 receptor agonists, DPP4 inhibitors and pioglitazone. For the choice of treatment, the following are taken into age ≥ 50 years, high blood pressure, dyslipidemia, obesity, smoking, and duration of diabetes.

AACE/ACE 2020. In 2020, a Consensus Statement [31] was published for the integrated treatment of type 2 diabetes from the American societies of endocrinology (American Association of Clinical Endocrinologists and American College of Endocrinology). It is recommended, regardless of glycemic control and from the first line, the use of an SGLT2 inhibitor or an agonist GLP1 receptor agonist with demonstrated clinical benefit in ASCVD or high cardiovascular disease risk, chronic renal failure (stage 3–4), heart failure with reduced ejection fraction.

KDIGO 2020. In the guidelines [32] of the Kidney Disease Improving Global Outcomes it is recommended that combination therapy should be used as first-line metformin and SGLT2 inhibitor in the patient with diabetes mellitus and disease chronic kidney disease (VFG between 60 and 30 mL/min and/or presence of albuminuria); if additional medication is needed to achieve the glycemic target may be added, with preference given to GLP1 receptor agonists with long acting.

ADA 2021. As early as 2020, the Standards of medical care of the ADA (American Diabetes Association) introduced the novelty of using agonists GLP1 receptor and SGLT2 inhibitors in patients with ASCVD or multiple risk factors for ASCVD, heart failure, and chronic kidney disease. Use should be considered in these patients regardless of the levels baseline HbA1c, target HbA1c, and metformin use (although this remains the first-line therapy for all patients). In the update of 2021 [33], the recommendation is further differentiated according to which the two classes of drugs mentioned above are alternative options in disease established cardiovascular disease or in the presence of multiple risk factors, while in heart failure with reduced ejection fraction or chronic kidney disease SGLT2 inhibitors are recommended in the first instance. As risk factors cardiovascular are identified as age ≥ 55 aa with left ventricular hypertrophy or coronary, carotid, or peripheral artery stenosis > 50%. AMD/SID 2021. Recent recommendations2 from the two scientific societies national identify 3 categories of patients with type 2 diabetes: (1) patients without previous cardiovascular events, (2) patients with previous cardiovascular events but without heart failure, and (3) patients with previous cardiovascular events and heart failure. For the former, the following are recommended: as the drug of first choice for initial therapy is metformin and, as second choice, inhibitors of SGLT2 and GLP1 receptor agonists; for the second category of patients, metformin, inhibitors of SGLT2 and GLP1 receptor agonists; finally, for patients with heart failure heart failure, only SGLT2 inhibitors are recommended as drugs of first choice, while metformin and GLP1 receptor agonists are second choice. DPP4 inhibitors are equated with other classes as drugs of second or third choice.

The introduction of Note 100 confirms metformin as the drug of first choice for the treatment of type 2 diabetes mellitus, unless contraindications or intolerance. The prescription of SGLT2i, GLP1-RA, DPP4i (in combination or as a substitute for other drugs) is provided if a treatment regimen containing metformin (alone or in combination) is not sufficient to the achievement/maintenance of the established individual goal of glycated hemoglobin (HbA1c). Note 100 also provides, in addition, indications preferential use between SGLT2i, GLP1-RA, and DPP4i in the patient with cardiovascular disease or chronic kidney disease or at high risk for cardiovascular disease. Note 100 allows the GP to prescribe the appropriate therapies necessary to manage the treatment of diabetes, even at a stage of suboptimal control, and to consider the need for possible evaluation by the specialist. Associations, extemporaneous or preconstituted, between drugs covered by the Note remain a specialist prescription as part of a more complex competence of the Centers dedicated to the treatment of diabetes.

Conclusion

The post-pandemic healthcare policies in Italy have highlighted the need for Health Systems to close to patients and to encourage general practitioners to prescribe new medications. Conversely, National Recovery and Resilience Plan (NRP) resources should be strategically allocated to strengthen networks of proximity healthcare for citizens and to expand health technologies, focusing on digitization to facilitate doctor-patient interactions. Consequently, any increase in healthcare expenditures directed towards prescribing and dispensing higher-cost drugs should be restrained following principles of appropriate prescription. Undoubtedly, policies aimed at simplifying patients’ access to healthcare are measures which represent a significant step towards an equitable healthcare approach. However, it is crucial to preserve the integrity of care appropriateness, avoids waste, and secures the sustainability of our healthcare system. Achieving this balance ensures that advancements in accessibility do not compromise the quality of care, thereby guaranteeing that healthcare system is responsive to the evolving needs of the population.

Author contribution

FF: Conceptualization, Writing - original draft, Methodology, Supervision, Validation.

AZ: Writing - review & editing MB: Supervision, Validation.

RL: Conceptualization, Writing - original draft.

EN: Supervision, Validation.

UT: Writing - review & editing MB: Supervision, Validation.

Data availability

Full availability of data and materials. All stated data can be provided on request to the reader.

Code availability

Not applicable.

Declarations

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The authors consent to the publication of the manuscript.

Competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare that the opinions expressed are of a personal nature and do not in any way commit the responsibility of the Administrations to which they belong.