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Editorial
Has the first treatment of type 2 diabetes mellitus changed?
¿Ha cambiado el primer tratamiento de la diabetes mellitus tipo 2?
Lilliam Flores
Corresponding author
lflores@clinic.cat

Corresponding author.
, Josep Vidal
Servicio de Endocrinología y Nutrición, Unidad de Obesidad, Hospital Clínic, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The aetiology of type 2 diabetes mellitus &#40;DM2&#41; is complex and involves numerous pathophysiological deficits affecting multiple organs&#46; Insulin resistance &#40;IR&#41; in the muscle and liver&#44; as well as &#946;-cell dysfunction&#44; are the main abnormalities responsible for the development and progression of hyperglycaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In addition&#44; IR is associated with other metabolic disorders&#44; such as obesity&#44; mainly visceral obesity&#44; hypertension&#44; dyslipidaemia&#44; endothelial dysfunction&#44; inflammation and a hypercoagulable state&#46; Each of these factors&#44; along with IR&#44; has been associated with the development of atherosclerotic cardiovascular disease&#44; which contributes to the increased risk of cardiovascular disease &#40;CVD&#41; in patients living with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It is generally agreed that CVD is the leading cause of morbidity and mortality in DM2&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> so numerous studies have made efforts to reduce CVD through achieving better glycaemic control&#46; However&#44; meta-analyses that include these studies show a rather modest reduction in major cardiovascular &#40;CV&#41; events&#44; with a greater benefit in non-fatal myocardial infarction&#44; with no significant effect on stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> On the other hand&#44; STENO-2&#44; which used a multifactorial approach but placed less emphasis on improving blood glucose and lowering haemoglobin A1c&#44; showed a significant reduction in both CV events and CV mortality&#46; Therefore&#44; it appears that treatment that is simply focused on hyperglycaemia and not on the concomitant management of the other IR syndrome components is unlikely to produce a sustained decrease in hyperglycaemia and decrease the risk of developing CVD&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The ideal treatment for DM2 is one that is able to reverse or halt at least eight of the pathophysiological deficits described in the <span class="elsevierStyleItalic">Ominous Octet</span> in the year 2009&#44; in which&#44; in addition to IR in the muscle &#40;decreased glucose uptake&#41;&#44; liver &#40;increased hepatic glucose production&#41; and progressive insufficiency of insulin secretion by the pancreatic &#946;-cells&#44; a dysfunction of &#945;-cells in the pancreas &#40;increased glucagon secretion&#41;&#44; IR of adipose tissue &#40;increased lipolysis&#41;&#44; decreased gastrointestinal incretin effect&#44; increased renal reabsorption of glucose and dysfunction of neurotransmitters in the brain &#40;decreased satiety&#41; are added&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This suggests that to prevent or delay progressive &#946;-cell insufficiency&#44; treatment should not simply be based on lowering A1c&#44; but may require&#44; along with lifestyle changes&#44; an early combination of drugs to correct the multiple known pathophysiological deficits&#46; In this sense&#44; for about 5 years there has been a paradigm shift in the management of DM2&#44; which recommends applying these modern concepts and guiding treatment according to the pathophysiology of the disease to achieve a benefit &#40;reduction of CVD&#41;&#44; as opposed to the classical approach of reaching a target &#40;A1c level&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Over the last two decades&#44; the vast majority of clinical guidelines have recommended metformin as first-line therapy in DM2 due to its efficacy&#44; low cost and well-established safety profile&#44; so the current debate focuses on whether we should replace this treatment in favour of the SGLT2 inhibitors &#40;sodium&#8211;glucose 2 cotransporter inhibitors&#41; and GLP-1 analogues &#40;glucagon-like peptide 1 receptor agonists&#41; which have recently demonstrated both CV safety and a reduction in major CV events &#40;including heart failure and renal protection&#41; in randomised clinical trials as part of the regulatory requirements for approval of new antidiabetic agents&#46; To guide treatment decisions in this patient population&#44; it would seem logical to have CV benefit studies with metformin and comparative studies between metformin and these new agents in both primary and secondary prevention&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">But what do we know about the CV benefits of metformin&#63; Although metformin is an oral antidiabetic drug that has been widely used for many years as a first-line treatment for DM2&#44; much of the evidence on CV outcomes comes from indirect comparative studies or sub-analyses of clinical trials designed to evaluate other antidiabetic treatments&#44; as well as studies comparing metformin with classic antidiabetic drugs that are no longer in use&#44; which limits the ability to extrapolate these results to routine clinical practice&#46; The CV benefits of metformin were demonstrated in 1998 in the UK Prospective Diabetes Study &#40;UKPDS&#41; substudy&#44; which included a small number of overweight patients with DM2 at low CV risk&#44; but showed CV benefits mainly in myocardial infarction&#44; diabetes-related death and all-cause mortality compared with conventional treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In addition&#44; when patients treated with metformin were compared to those treated with sulphonylureas or insulin&#44; patients on metformin treatment showed less diabetes-related complications&#44; lower overall mortality and a benefit in stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">On the other hand&#44; it should be noted that the trials of SGLT2 inhibitors<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> and GLP-1 analogues<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;14</span></a> that have shown safety and CV benefits &#40;Cardiovascular Outcome Trials &#91;CVOT&#93;&#41; were conducted in patients with DM2 at high CV risk&#44; the majority of whom had established CVD &#40;population other than the UKPDS&#41; and were already receiving standard treatment&#44; which generally included metformin &#40;70&#37;&#8211;80&#37;&#41;&#44; so that the benefits observed with these drugs were mostly in combination with metformin&#46; To understand how these drugs interact with each other and whether they may have synergistic or antagonistic effects on CV outcomes&#44; some CVOTs with these drugs have conducted post hoc analyses to investigate whether metformin modifies the observed protective effect&#44; with conflicting results&#46; In the <span class="elsevierStyleItalic">post-hoc</span> analysis of the Liraglutide Effect and Action in Diabetes&#58; Evaluation of Cardiovascular Outcome Results &#40;LEADER&#41; study&#44; in which 76&#37; of patients were using metformin&#44; it was observed that patients who were not using metformin at baseline experienced more pronounced CV benefits compared to those who were using metformin&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In contrast&#44; the efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide &#40;HARMONY&#41; study&#44; with 73&#37; of patients on metformin treatment&#44; showed a significant CV benefit of albiglutide in patients on metformin treatment at baseline&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Among the SGLT2 inhibitors&#44; the hazard ratios in the Empagliflozin&#44; Cardiovascular Outcomes&#44; and Mortality in type 2 diabetes &#40;EMPA-REG&#41; and Canagliflozin and Cardiovascular and Renal Event in type 2 diabetes &#40;CANVAS&#41; studies suggested that the CV benefit observed was mainly due to the CV benefit obtained in patients who were not receiving metformin treatment at baseline&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> However&#44; it is important to remember the limitations of <span class="elsevierStyleItalic">post hoc</span> analyses and that the results should be interpreted with caution&#46; Regarding secondary prevention&#44; given the current evidence and the ethical principles of beneficence and non-maleficence&#44; it will not be possible to conduct trials comparing metformin with placebo in this group of patients&#46; In primary prevention&#44; a recent meta-analysis of 30 CVOTs &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>225&#44;305&#41; with GLP-1 analogues and SGLT2 inhibitors showed a reduction in the risk of major adverse cardiovascular events &#40;MACE&#41; that was consistent across CVD patients&#46; &#40;HR&#58; 0&#46;87&#59; CI 95&#37;&#58; 0&#46;83&#8211;0&#46;92&#41; and without CVD &#40;HR&#58; 0&#46;92&#59; CI 95&#37;&#58; 0&#46;83&#8211;1&#46;02&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> As regards metformin&#44; there is only one ongoing active comparator trial to assess the superiority of dapagliflozin versus metformin as first-line treatment in patients with DM2<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>4 years in reducing CV events &#40;Clinicaltrials&#46;gov&#58; NCT03982381&#41;&#44; with an estimated completion date of October 2025&#46; In summary&#44; the evidence for metformin as a cardioprotective agent is less consistent and robust than that for SGLT2 inhibitors and GLP-1 analogues&#44; but what impact have the CVOT results with GLP-1 analogues and SGLT2 inhibitors had on clinical guidelines&#63;</p><p id="par0035" class="elsevierStylePara elsevierViewall">These studies have led to a process of continuous updating of clinical guidelines for the management of DM2&#46; The consensus published in 2018 proposed by the American Diabetes Association &#40;ADA&#41; and the European Association for Study of Diabetes &#40;EASD&#41; laid the groundwork for a significant change in the approach to DM2 by highlighting the importance of CVD prevention and personalisation of treatment to improve clinical outcomes in patients&#46; This approach has continued to evolve in subsequent recommendations from other medical organisations and societies&#44; such as the European Society of Cardiology &#40;ESC&#41; and EASD in 2019 and the ESC in 2023&#44; further reinforcing the paradigm shift in the management of DM2 towards a holistic&#44; patient-centred approach&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The ADA 2024 recommendations for the management of DM2 consolidate the personalised approach and include guidelines stratified by CV risk&#46; These guidelines recommend considering GLP-1 analogues and SGLT2 inhibitors as first-line treatments&#44; regardless of glycaemic control&#44; in patients with established CVD&#44; heart failure and&#47;or chronic kidney disease&#46; In addition&#44; ADA suggests that initial combination therapy should be considered in people with elevated A1c levels&#44; and metformin&#44; SGLT2 inhibitors or GLP-1 analogues are recommended as long-term first-line treatment for patients with DM2 and prior CV events&#44; but without heart failure&#46; As second-line treatment&#44; DPP-4 inhibitors&#44; pioglitazone&#44; acarbose and insulin should be considered&#46; In patients with DM2 who have had previous heart failure&#44; SGLT-2 inhibitors are recommended as long-term first-line treatment&#46; Finally&#44; and for the first time&#44; the ADA Standards of Care 2024 emphasise the importance of weight control as an integral part of DM2 management&#46; The implications of the ADA 2024 recommendations for the use of metformin as first-line therapy in DM2 include a change in the approach to initiation to one that is personalised and tailored&#44; taking into account individual patient characteristics and comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Recognising the CV benefits of GLP-1 analogues and SGLT2 inhibitors has had a major impact on clinical practice in the management of DM2 and CVD in general&#44; with a shift in treatment recommendations to prioritise consideration of these drugs in patients with established CVD or multiple CV risk factors&#44; with a broader focus on primary and secondary prevention of major CV events and on reducing the risk of hospitalisation for heart failure&#44; with a greater emphasis on the CV risk profile of patients when selecting drugs for the treatment of DM2&#44; and an impact on multidisciplinary care with increased collaboration between diabetes specialists&#44; cardiologists and other healthcare professionals in the comprehensive management of patients with DM2 and CVD&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In view of the above&#44; it does not seem justifiable to continue to consider metformin as a universal first-line treatment for all patients with DM2&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">Both authors declare that they have no potential conflicts of interest&#46;</p></span></span>"
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ISSN: 23870206
Original language: English
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