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2022 update to the position statement by Primary Care Diabetes Europe: a disease state approach to the pharmacological management of type 2 diabetes in primary care

Open AccessPublished:February 16, 2022DOI:https://doi.org/10.1016/j.pcd.2022.02.002

      Highlights

      • Primary care professionals face growing complexity of treatment options.
      • This consensus recommends a simple, evidence-based CV risk stratification rubric.
      • HCPs should consider early combination options for people with various comorbidities.
      • A comprehensive summary of prescribing tips and side effects by drug class is given.

      Abstract

      Type 2 diabetes and its associated comorbidities are growing more prevalent, and the complexity of optimising glycaemic control is increasing, especially on the frontlines of patient care. In many countries, most patients with type 2 diabetes are managed in a primary care setting. However, primary healthcare professionals face the challenge of the growing plethora of available treatment options for managing hyperglycaemia, leading to difficultly in making treatment decisions and contributing to treatment and therapeutic inertia. This position statement offers a simple and patient-centred clinical decision-making model with practical treatment recommendations that can be widely implemented by primary care clinicians worldwide through shared-decision conversations with their patients. It highlights the importance of managing cardiovascular disease and elevated cardiovascular risk in people with type 2 diabetes and aims to provide innovative risk stratification and treatment strategies that connect patients with the most effective care.

      Keywords

      1. Statement of intent

      New and emerging medical therapies and evidence have changed the landscape for managing people with type 2 diabetes (T2D) with established cardiovascular disease (CVD) and those with cardiovascular risk factors. Previously, guidelines gauged good diabetes care primarily based on glycated haemoglobin (HbA1c) targets [
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • Diamant M.
      • Ferrannini E.
      • Nauck M.
      • Matthews D.R.
      Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ], but recent updates have represented a major shift, now recommending a multimorbidity risk management approach, mainly based on cardiovascular outcome trials (CVOTs). Effective glycaemic control also remains an important consideration for prevention or improvement of microvascular disease. The reality of primary care necessitates an increasingly holistic and integrated care approach for optimal patient management [
      • Bodenheimer T.
      • Wagner E.H.
      • Grumbach K.
      Improving primary care for patients with chronic illness: the chronic care model, part 2.
      ,
      • Hambling C.E.
      • Khunti K.
      • Cos X.
      • Wens J.
      • Martinez L.
      • Topsever P.
      • Seidu S.
      Factors influencing safe glucose-lowering in older adults with type 2 diabetes: a PeRsOn-centred ApproaCh To IndiVidualisEd (PROACTIVE) Glycemic Goals for older people: a position statement of Primary Care Diabetes Europe.
      ].
      This position statement, written by primary care practitioners (PCPs) and for PCPs, supports a comprehensive disease state approach to clinical decision making in management of patients with T2D. It is intended to provide a simple and effective guide to evaluate cardiovascular risk in people with T2D managed in primary care, and clear and practical treatment recommendations that can be useful for healthcare professionals (HCPs) globally who manage people with diabetes in a primary care setting. The role of primary care professionals as frontline clinicians in chronic disease management varies worldwide. While every country will have its own treatment realities, this position statement aims to provide a critical interpretation of the best available evidence and a unique tool to facilitate its application in primary care clinical decision making. The guiding scientific principles will be applied differently, contingent on treatment access and the financial or economic limitations of patients and their country-specific healthcare systems [
      • European Coalition for Diabetes
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      ,
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      • Duncan B.B.
      • Mbanya J.C.
      IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.
      ].

      2. Introduction and rationale

      The severe burden of T2D is recognised globally [
      • Blaslov K.
      • Naranđa F.S.
      • Kruljac I.
      • Renar I.P.
      Treatment approach to type 2 diabetes: past, present and future.
      ], accounting for approximately 90% of the 537 million estimated diabetes cases worldwide [
      • Sun H.
      • Saeedi P.
      • Karuranga S.
      • Pinkepank M.
      • Ogurtsova K.
      • Duncan B.B.
      • Mbanya J.C.
      IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.
      ]. Diabetes can be successfully managed, and its associated complications prevented, especially if detected and treated early [
      • Khunti K.
      • Seidu S.
      Therapeutic inertia and the legacy of dysglycemia on the microvascular and macrovascular complications of diabetes.
      ]. Understanding the complexity of the disease and the pharmacological options is critical for ensuring optimal patient care and improving outcomes.
      When not treated in a timely and effective manner, poorly managed T2D is associated with life-threatening complications, including chronic kidney disease (CKD), amputations, blindness and CVD [
      • Gregg E.W.
      • Sattar N.
      • Ali M.K.
      The changing face of diabetes complications.
      ,
      • Narayan K.M.V.
      • Gujral U.P.
      Evidence tips the scale toward screening for hyperglycemia.
      ]. The presence of multimorbidity is the reality for the vast majority of patients with T2D. CVD affects about 30% of all people with T2D [
      • Einarson T.R.
      • Acs A.
      • Ludwig C.
      • Panton U.H.
      Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017.
      ] and is a major cause of morbidity and mortality [
      • Sun H.
      • Saeedi P.
      • Karuranga S.
      • Pinkepank M.
      • Ogurtsova K.
      • Duncan B.B.
      • Mbanya J.C.
      IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.
      ]. Thus, a comprehensive diabetes management plan for both the primary and secondary prevention of CVD is important for educating patients to make informed decisions that will help them succeed in reaching their glycaemic target goals and prevent the number and complexity of serious complications [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].
      As experts in ‘whole-person medicine’, primary care physicians are tasked with using their generalist expertise to work with their patients to develop a comprehensive treatment plan that addresses all of their health needs and goals. Indeed, an evidence-based generalist approach has been suggested as the way forward to address the complex challenges of multimorbidity and avoid the pitfalls of treating each disease state in isolation [
      • Reeve J.
      • Blakeman T.
      • Freeman G.K.
      • Green L.A.
      • James P.A.
      • Lucassen P.
      • van Weel C.
      Generalist solutions to complex problems: generating practice-based evidence - the example of managing multi-morbidity.
      ]. Access to patient-centred care can significantly improve outcomes for people with T2D, and this process begins at the level of primary care. The majority of routine T2D management occurs in primary care [
      • Rushforth B.
      • McCrorie C.
      • Glidewell L.
      • Midgley E.
      • Foy R.
      Barriers to effective management of type 2 diabetes in primary care: qualitative systematic review.
      ], as part of the chronic care model which focuses on an integrated multidisciplinary team approach involving specialists, dieticians, nurses and other allied HCPs [
      • Bodenheimer T.
      • Wagner E.H.
      • Grumbach K.
      Improving primary care for patients with chronic illness: the chronic care model, part 2.
      ,
      • Rutten G.E.H.M.
      • Vugt H.A.v.
      • Weerdt I.d.
      • Koning E.d.
      Implementation of a structured diabetes consultation model to facilitate a person-centered approach: results from a Nationwide Dutch Study.
      ,
      • Vugt H.A.v.
      • Koning E.J.P.d.
      • Rutten G.E.H.M.
      Association between person and disease related factors and the planned diabetes care in people who receive person-centered type 2 diabetes care: an implementation study.
      ]. While nurses play a central role in primary care, their degree of professional involvement and utilisation can vary widely across different healthcare systems [
      • Norful A.
      • Martsolf G.
      • de Jacq K.
      • Poghosyan L.
      Utilization of registered nurses in primary care teams: a systematic review.
      ,
      • Jeavons D.
      Patients with poorly controlled diabetes in primary care: healthcare clinicians’ beliefs and attitudes.
      ]. Nonetheless, patients continue to benefit from comprehensive care, as family physicians and general practitioners are able to provide timely and informed treatment recommendations based on their clinical expertise in both chronic and acute condition management and an effective patient–physician relationship enabled by continuity of care [
      • Seidu S.
      • Davies M.J.
      • Farooqi A.
      • Khunti K.
      Integrated primary care: is this the solution to the diabetes epidemic?.
      ]. Primary care physicians are uniquely placed to adopt shared decision making models of care, where HCPs and patients co-develop treatment goals through dialogue and with reference to the benefits and risks of different treatment options [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Rutten G.E.H.M.
      • Vugt H.A.v.
      • Weerdt I.d.
      • Koning E.d.
      Implementation of a structured diabetes consultation model to facilitate a person-centered approach: results from a Nationwide Dutch Study.
      ]. These conversations should also address treatment access, drug cost, adverse events, reimbursement options and local prescribing guidelines.
      In spite of this, an increasing number of HCPs struggle with therapeutic inertia when treating diabetes [
      • Khunti S.
      • Khunti K.
      • Seidu S.
      Therapeutic inertia in type 2 diabetes: prevalence, causes, consequences and methods to overcome inertia.
      ,
      • Khunti K.
      • Gomes M.B.
      • Pocock S.
      • Shestakova M.V.
      • Pintat S.
      • Fenici P.
      • Medina J.
      Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: a systematic review.
      ,
      • van Bruggen R.
      • Gorter K.
      • Stolk R.
      • Klungel O.
      • Rutten G.
      Clinical inertia in general practice: widespread and related to the outcome of diabetes care.
      ]. Moreover, there is room for improvement in the control of risk factors in people with T2D worldwide [
      • Stone M.A.
      • Charpentier G.
      • Doggen K.
      • Kuss O.
      • Lindblad U.
      • Kellner C.
      • G.S.G. On behalf of the
      Quality of care of people with type 2 diabetes in Eight European Countries: findings from the Guideline Adherence to Enhance Care (GUIDANCE) study.
      ,
      • Zhang N.
      • Yang X.
      • Zhu X.
      • Zhao B.
      • Huang T.
      • Ji Q.
      Type 2 diabetes mellitus unawareness, prevalence, trends and risk factors: National Health and Nutrition Examination Survey (NHANES) 1999–2010.
      ]. The clinical decision process in primary care is exceedingly complex, and some PCPs may struggle to maintain up-to-date knowledge in a changing scientific landscape and with limited resources available to care for their patients. Research identifies a lack of adherence to treatment guidelines among these challenges, resulting in delayed or inappropriate therapy advancement [
      • Santos Cavaiola T.
      • Kiriakov Y.
      • Reid T.
      Primary care management of patients with type 2 diabetes: overcoming inertia and advancing therapy with the use of injectables.
      ] and failure to meet guideline-recommended targets [
      • Khunti K.
      • Ceriello A.
      • Cos X.
      • De Block C.
      Achievement of guideline targets for blood pressure, lipid, and glycaemic control in type 2 diabetes: a meta-analysis.
      ]. Patients often lack clear and personalised healthcare agendas because of clinicians’ concerns related to medication issues, the complexity of creating tailored treatment plans for patients with multimorbidity, and in some instances, budget constraints. Patients also struggle with adherence to medication regimens, particularly when treated with multiple agents [
      • van Bruggen R.
      • Gorter K.
      • Stolk R.P.
      • Zuithoff P.
      • Klungel O.H.
      • Rutten G.E.H.M.
      Refill adherence and polypharmacy among patients with type 2 diabetes in general practice.
      ]. Other issues, such as social determinants of health, remain significant barriers to treatment improvement and access [
      • Silva-Tinoco R.
      • Cuatecontzi-Xochitiotzi T.
      • De la Torre-Saldaña V.
      • León-García E.
      • Serna-Alvarado J.
      • Guzmán-Olvera E.
      • Prada D.
      Role of social and other determinants of health in the effect of a multicomponent integrated care strategy on type 2 diabetes mellitus.
      ]. Despite these challenges, high-quality diabetes care has been shown to be achievable in the primary care setting [
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.H.M.
      • Sandbæk A.
      • Lauritzen T.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      ,
      • Griffin S.J.
      • Rutten G.E.H.M.
      • Khunti K.
      • Witte D.R.
      • Lauritzen T.
      • Sharp S.J.
      • Sandbæk A.
      Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial.
      ]. As such, training in optimal use of available therapies and primary care-specific treatment guidelines are necessary to overcome therapeutic inertia, improve T2D control and prevent complications.
      The paucity of randomised controlled trials (RCTs) carried out in primary care populations has served as a potential barrier for the development of treatment guidelines and tools specific for primary care [
      • Starfield B.
      • Shi L.
      • Macinko J.
      Contribution of primary care to health systems and health.
      ]. Even though there has been an increase in the proportion of diabetes research outputs from primary care in recent years, this still lags significantly behind the total research output in diabetes (0.5% in 1996 and 2.2% in 2016) [
      • Khunti K.
      • Seidu S.
      Diabetes research in primary care: fiction, reality or essential?.
      ].
      Moreover, the full patient population treated in primary care often differs widely from those who meet the inclusion criteria of clinical trials, with the relevant primary care population typically being older and displaying greater multimorbidity than patients included in RCTs [
      • Saunders C.
      • Byrne C.D.
      • Guthrie B.
      • Lindsay R.S.
      • McKnight J.A.
      • Philip S.
      • G. Scottish Diabetes Research Network Epidemiology
      External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants?.
      ,
      • McGovern A.
      • Feher M.
      • Munro N.
      • de Lusignan S.
      Sodium-glucose co-transporter 2 (SGLT2) inhibitor: comparing trial data and real-world use.
      ,
      • Birkeland K.I.
      • Bodegard J.
      • Norhammar A.
      • Kuiper J.G.
      • Georgiado E.
      • Beekman‐Hendriks W.L.
      • Kooy A.
      How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study.
      ,
      • Wittbrodt E.T.
      • Eudicone J.M.
      • Bell K.F.
      • Enhoffer D.M.
      • Latham K.
      • Green J.B.
      Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population.
      ], making it challenging to apply these data to everyday practice. Thus, more research is needed to strengthen the capacity of primary care teams to overcome the diabetes epidemic.

      2.1 Purpose of position statement

      A tremendous volume of high-quality, evidence-informed treatment guidelines for the management of T2D exist and have been widely distributed. While these guidelines have had a profound influence in promulgating clinical practice decisions, they may be too detailed and exhaustive for primary care clinicians. Recent consensus guidelines with complex treatment algorithms for people with T2D and established or risk of CVD have shown greater focus towards a target audience of secondary care specialists, rather than frontline clinicians [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Bain S.C.
      • Bakhai A.
      • Evans M.
      • Green A.
      • Menown I.
      • Strain W.D.
      Pharmacological treatment for Type 2 diabetes integrating findings from cardiovascular outcome trials: an expert consensus in the UK.
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • Chowdhury T.A.
      2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ]. In addition, most guidelines lack specific recommendations for patient referral to secondary care [
      • F. International Diabetes
      IDF Clinical Practice Recommendations for managing Type 2 Diabetes in Primary Care.
      ]. Significant strides have been made in some countries to include the primary care perspective in guideline development, and this position statement aims to complement these efforts and to provide useful guidance for regions where primary care guideline input is lacking.
      This position statement aims to provide a simple and pragmatic tool for primary care clinicians and other HCPs worldwide for the pharmacological management of people with T2D and other comorbidities in their role as first point of contact in healthcare. This document will also include a selection of some useful online resources on how to manage T2D in the virtual consultation setting in response to the COVID-19 pandemic impact on the delivery of care. This patient-centred clinical decision-making approach is unique from most of the existing national and international guidelines. It offers a novel risk stratification approach and practical recommendations that can be widely implemented through various primary care systems to help link patients with the appropriate care and prevent diabetes-associated complications. It is not intended to supplant well-established national and international guidelines, but rather to provide additional direction and focus to reflect primary care in high-risk patients with T2D. In addition, this consensus paper draws increasing attention to heart failure and cardiorenal syndrome as serious comorbidities associated with T2D.
      Box 1 summarises suggestions on how primary care physicians can use this position statement to drive shared decision-making conversations with their patients. Box 2 introduces new, evidence-based criteria for cardiovascular risk stratification of patients with T2D in primary care. Throughout the paper, the key recommendations are collected in callout boxes for easy reference.
      How to use this position statement.
      This position statement summarises the current evidence for glycaemic efficacy, cardiovascular and renal risk, and side effects for a wide variety of therapies for T2D.
      Box 2 suggests a simple and pragmatic cardiovascular risk assessment to help inform patient-centred treatment decisions.
      Boxes 3–8Box 3 summarise the treatment recommendations by cardiovascular/renal disease or risk factor.
      Table 1 summarises the prescribing tips and side effects related to each drug class discussed.
      Cardiovascular risk stratification in patients with T2D
      Patients with T2D are considered to be at very high cardiovascular risk if they have any of the following:
      • 1
        History of CVD (A)
      • 2
        Multiple uncontrolled CVD risk factors, including hypertension, hyperlipidaemia, obesity, smoking and/or physical inactivity (A)
      • 3
        Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (B)
      • 4
        Albuminuria (B)
      • 5
        Age at diagnosis <40 years (C)
      All other patients with T2D, including patients ≥65 years, are considered to be at high cardiovascular risk
      Letters (A–C) denote level of evidence based on the American Diabetes Association grading system: A, clear evidence from well-conducted, generalisable RCTs, that are adequately powered, including 1) evidence from a well-conducted multicentre trial or meta-analysis that incorporated quality ratings in the analysis, 2) compelling nonexperimental evidence, 3) supportive evidence from well-conducted RCTs that are adequately powered; B, supportive evidence from a well-conducted cohort study or case-control study; C, supportive evidence from poorly controlled or uncontrolled studies, or conflicting evidence with the weight of evidence supporting the recommendation; E, expert opinion.

      3. Methods

      This position statement is authored by a group of PCPs convened by Primary Care Diabetes Europe. A comprehensive review of international diabetes guidelines was conducted at a roundtable consensus conference in February 2019, following which the evidence was updated in 2021. The overall author group consisted of 9 primary care clinicians and 1 nurse with expertise in diabetes representing the European and North American regions. Facilitated by an independent moderator, consensus was reached between all members of the author group on the focus of the position statement and its general framework by using a nominal group technique [
      • Mc Sharry J.
      • Fredrix M.
      • Hynes L.
      • Byrne M.
      Prioritising target behaviours for research in diabetes: using the nominal group technique to achieve consensus from key stakeholders.
      ]. Using a Likert scale (of ‘strongly disagree’, ‘disagree’, ‘agree’, and ‘strongly agree’), a consensus was achieved when agreement exceeded 90% of the votes.
      To assess the currently available research on people with diabetes in primary care, a PubMed literature search was conducted in advance of the consensus conference on epidemiological studies carried out in primary care populations and with the involvement of primary care clinicians within the last 5 years. These results were shared at the consensus conference, followed by a series of presentations organised by drug family [

      W.H. Organization, WHOCC - ATC/DDD Index.

      ]. Each individual presentation replicated a common format, from discussing the different compound options available within each family, to a detailed review of current evidence supporting the use of each compound/drug family in the primary and secondary prevention of CVD in patients with T2D. These presentations helped to lay the foundational knowledge for further discussion on the gaps in existing guidelines and the need for specific treatment recommendations for primary care clinicians.

      3.1 Synthesis of the position statement

      To assess the most recent data on optimal treatment of T2D, a detailed and focused literature review (Medline, Web of Science, Google Scholar, and Ebsco CINAHL. EMBASE was not included in this search) was undertaken to identify English language articles published since 2015. Search terms included, but were not limited to, ‘type 2 diabetes’, ‘cardiovascular disease’, ‘global health’, ‘prevalence’, ‘primary care’, ‘therapeutic adherence’ and ‘therapeutic inertia’. Given the breadth of this consensus statement, review articles were also included. Recommendations are based on rigorous and careful review of the evidence regarding the efficacy on clinically important outcomes and adverse effects of available medications. Additional landmark studies and publications were suggested by the authors. The authors discussed the identified literature and assessed its relevance using the consensus approach outlined above.
      This consensus statement was drafted with the support of a writing group, followed by cycles of review and revision of the manuscript. The focus of the position statement and section headings were further refined through various rounds of correspondence until consensus was reached between all members of the author group. A draft was reviewed at a second author group meeting in September 2019 to discuss and collect additional feedback. Review of the updated draft was then invited by a diabetologist and a primary care physician external to the consensus statement process and their comments considered by the authors. In May 2021, substantial new evidence had come into light since the initial publication of this position statement. This evidence was compelling enough to demand an additional round of review and discussion and led to the update of this consensus statement, which includes a summary of the recently published evidence.

      4. Visual patient assessment checklist and prescribing tips by drug class

      Fig. 1 shows a visual summary of the recommendations of this position statement. More information for the summarised recommendations can be found in Section 6.
      Fig. 1
      Fig. 1Visual patient assessment checklist.
      Reference in support of these recommendations can be found in Section . Treatment recommendations stratified by disease condition. ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular, CVD, cardiovascular disease; DPP-4is. dipeptidy peptidase-4 inhibitors; eGFR, estimated glomerular filtration rate; GLP-1RAs, glucagon-like peptide-1 receptor agonists; HF, heart failure; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatis; SGLT-2is, sodium-glucose co-transporter-2 inhibitors; SUs, sulphonylureas; T2D, type 2 diabetes.
      Some general principles, such as avoiding hypoglycaemia, focusing on cardiovascular prevention, individualising control targets, assessing therapeutic adherence, avoiding therapeutic inertia, acknowledging the importance of patient-perceived outcomes (e.g., weight loss), and considering patients' preferences and values, should be considered when treating patients with T2D [
      • Álvarez-Guisasola F.
      • Orozco-Beltrán D.
      • Cebrián-Cuenca A.M.
      • Quintero M.A.R.
      • Martínez E.A.
      • Lachica L.Á.
      • Perez J.S.
      Manejo de la hiperglucemia con fármacos no insulínicos en pacientes adultos con diabetes tipo 2.
      ].
      Side effects are major factors influencing treatment choice and medication adherence [
      • Polonsky W.
      • Henry R.
      Poor medication adherence in type 2 diabetes: recognizing the scope of the problem and its key contributors.
      ]. Patients will have their personal needs, preferences, and tolerances regarding the route of administration (injectable or oral), discomfort, side effects, and the price they are willing to pay out of pocket. Shared decision making is an approach in which patients and clinicians work together and engage in a deliberate dialogue about reasonable treatment options. In this process, the HCP is the expert in evidence-based medicine and should suggest the most clinically appropriate and safe medications. This approach is feasible in primary care [
      • Rutten G.E.H.M.
      • Vugt H.A.v.
      • Weerdt I.d.
      • Koning E.d.
      Implementation of a structured diabetes consultation model to facilitate a person-centered approach: results from a Nationwide Dutch Study.
      ]. Table 1 summarises the most common and serious side effects that should be taken into consideration when choosing the most appropriate treatment regimen, as well as relevant prescribing tips to ensure minimal occurrence or impact of these side effects.
      Table 1Side effects of concern and prescribing tips for the use of antidiabetic medications in the treatment of type 2 diabetes.
      Chemical substance or chemical subgroupPhysiological mode of actionSide effects of concernPrescribing tips
      MetforminDecreases hepatic glucose production [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      GI symptoms [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      GI symptoms during therapy initiation appear to be dose-related, and they may be decreased by gradual dose escalation and by taking the medicine with meals [
      • I. Sanofi-Aventis Canada
      Glucophage Product Monograph.
      ]
      GlinidesIncrease insulin secretion [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Modest weight gain, low risk of hypoglycaemia [
      • Guardado-Mendoza R.
      • Prioletta A.
      • Jiménez-Ceja L.M.
      • Sosale A.
      • Folli F.
      The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.
      ]
      GLP-1 receptor agonistsEnhance glucose-dependent insulin production, suppress glucose-dependent glucagon secretion, slow gastric emptying,

      suppress appetite [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      GI symptoms including nausea, diarrhoea, vomiting, decreased appetite, abdominal pain, constipation. These may also include a possible increased risk of acute pancreatitis (which is listed as very rare or uncommon) [
      • A.S. Novo Nordisk
      Victoza (liraglutide) Prescribing Information.
      ,
      • A.S. Novo Nordisk
      Ozempic (semaglutide) Prescribing Information.
      ]

      An increased risk of diabetic retinopathy was observed with semaglutide in SUSTAIN 6 trial [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jódar E.
      • Leiter L.A.
      • Vilsbøll T.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]
      GI symptoms may happen initially, but they are transitory and often mild to moderate. If patients do not tolerate a gradual dose escalation, consider returning the patient to a lower dose for one week or more before trying again to increase the dose. It is also recommended to have healthy, non-spicy, and smaller meals to reduce the risk of nausea [
      • Romera I.
      • Cebrian-Cuenca A.
      • Alvarez-Guisasola F.
      • Gomez-Peralta F.
      • Reviriego J.
      A review of practical issues on the use of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetes.
      ]

      Patients are advised to use a different injection site each week to avoid injection site reactions [
      • C. AstraZeneca
      Exenatide Product Information.
      ]
      SGLT-2 inhibitorsEnhance excretion and prevent reabsorption of urinary glucose [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Urogenital tract infections (with higher risk in women and potential greater impact on quality of life in the elderly). Dehydration, hypotension from increased urination, and risk of lower limb amputations are considered uncommon, except for volume depletion with ertugliflozin, which is listed as common [
      • Engelhardt K.
      • Ferguson M.
      • Rosselli J.L.
      Prevention and management of genital mycotic infections in the setting of sodium-glucose cotransporter 2 inhibitors.
      ,
      • I. Janssen Pharmaceuticals
      Invokana (canagliflozin) Prescribing Information.
      ,
      • C. AstraZeneca
      Forxiga (dapagliflozin) [summary of product characteristics].
      ,
      • P. Boehringer Ingelheim
      Jardiance (empagliflozin) Prescribing Information.
      ,
      • Lega I.C.
      • Bronskill S.E.
      • Campitelli M.A.
      • Guan J.
      • Stall N.M.
      • Lam K.
      • Rochon P.A.
      Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: a population-based study of older women and men with diabetes.
      ,
      • Hsia D.S.
      • Grove O.
      • Cefalu W.T.
      An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus.
      ,

      M.S.D. B.V, Steglatro (ertugliflozin) [summary of product characteristics].

      ]
      Monitor and treat urogenital infections as needed

      In conditions of reduced oral intake, or potential fluid losses, such as gastrointestinal illness, carefully monitor volume status and discontinue treatment until fluid loss is corrected [
      • I. Janssen Pharmaceuticals
      Invokana (canagliflozin) Prescribing Information.
      ,
      • C. AstraZeneca
      Forxiga (dapagliflozin) [summary of product characteristics].
      ,
      • P. Boehringer Ingelheim
      Jardiance (empagliflozin) Prescribing Information.
      ,

      M.S.D. B.V, Steglatro (ertugliflozin) [summary of product characteristics].

      ,

      G.G. GmbH, Zynquista (sotagliflozin) [summary of product characteristics], in.

      ]

      If administering canagliflozin, be cautious of other pre-existing factors that could increase fracture risk, such as history of fractures and higher risk of falls, as bone fracture is listed as uncommon for this chemical substance [
      • I. Janssen Pharmaceuticals
      Invokana (canagliflozin) Prescribing Information.
      ]

      Encourage proper hygiene in both female and male patients to avoid genital mycotic infections [
      • Engelhardt K.
      • Ferguson M.
      • Rosselli J.L.
      Prevention and management of genital mycotic infections in the setting of sodium-glucose cotransporter 2 inhibitors.
      ]
      DPP-4 inhibitorsEnhance glucose-dependent insulin production, suppress glucose-dependent glucagon secretion [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Upper respiratory tract infection, urinary tract infection, nasopharyngitis and headache [
      • Merck, I. Co
      Januvia (sitagliptin) Prescribing Information.
      ,

      A. AB, Onglyza (saxagliptin) [summary of product characteristics], in.

      ,

      B.I.I. GmbH, Trajenta (linagliptin) [summary of product characteristics].

      ], neutral effect on macrovascular and microvascular complications, with the exception of saxagliptin, which may increase the risk for HF hospitalisations [
      • Taylor O.M.
      • Lam C.
      The effect of dipeptidyl peptidase-4 inhibitors on macrovascular and microvascular complications of diabetes mellitus: a systematic review.
      ]
      SulphonylureasIncrease insulin secretion [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Hypoglycaemia, weight gain [
      • Sola D.
      • Rossi L.
      • Schianca G.P.C.
      • Maffioli P.
      • Bigliocca M.
      • Mella R.
      • Derosa G.
      State of the art paper Sulfonylureas and their use in clinical practice.
      ]
      Hypoglycaemia usually occurs due to excessive dosage; use with caution in situations in which hypoglycaemia is most likely to occur. Weight gain is usually countered by the concurrent administration of metformin [
      • Sola D.
      • Rossi L.
      • Schianca G.P.C.
      • Maffioli P.
      • Bigliocca M.
      • Mella R.
      • Derosa G.
      State of the art paper Sulfonylureas and their use in clinical practice.
      ]

      Only gliclazide may be used in CKD stage 3 or worse. For all others, dose should be reduced in subjects with eGFR 60–90 mL/min/1.73 m2. Contraindicated in subjects with eGFR <60 mL/min/1.73 m2[
      • Jonsson A.
      • Rydberg T.
      • Melander A.
      • Sterner G.
      Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function.
      ].

      Even in the case of gliclazide, a hypoglycaemic episode occurring in these patients may be prolonged, so appropriate management should be initiated
      AcarboseReduces rate of absorption of carbohydratesFlatulence, mild diarrhoeaSide effects may be mitigated if the dose is increased slowly [
      • van de Laar F.A.
      • Lucassen P.L.
      • Akkermans R.P.
      • van de Lisdonk E.H.
      • Rutten G.E.
      • van Weel C.
      Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis.
      ]
      PioglitazoneEnhances insulin sensitivity [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Weight gain, swelling, risk of bone fracture, bone loss [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Shah P.
      • Mudaliar S.
      Pioglitazone: side effect and safety profile.
      ]

      Should not be used in patients with history of or active bladder cancer [
      • Lewis J.D.
      • Ferrara A.
      • Peng T.
      • Hedderson M.
      • Bilker W.B.
      • Quesenberry C.P.
      • Strom B.L.
      Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study.
      ] or those at risk of HF [
      • Nesto R.W.
      • Bell D.
      • Bonow R.O.
      • Fonseca V.
      • Grundy S.M.
      • Horton E.S.
      • Kahn R.
      Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association.
      ]
      InsulinStimulates insulin receptor leading to increased insulin disposal and decreased production of glucose [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      Hypoglycaemia, weight gain [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ]
      If hypoglycaemia develops, consider reducing dose or modifying timing of injection. Patients should be encouraged to rotate injection sites
      DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; HF, heart failure; SGLT-2, sodium-glucose co-transporter-2.

      4.1 Managing T2D in the virtual consultation setting

      Telemedicine has emerged as a must-use method in the delivery of care during the COVID-19 pandemic. It has shown that remote consultation can improve the quality of primary care and be effectively used for forwarding patients to COVID-19 triage before face-to-face consultation [
      • Mold F.
      • Hendy J.
      • Lai Y.-L.
      • de Lusignan S.
      Electronic consultation in primary care between providers and patients: systematic review.
      ,
      • Hollander J.E.
      • Carr B.G.
      Virtually perfect? Telemedicine for Covid-19.
      ]. On the other hand, the experience during the pandemic also pointed out possible pitfalls of the virtual consultation setting. Negligence of the essential first-contact role with primary care professionals happened due to the hegemony of pandemic health services. This led to missed opportunities for preventative care not related to COVID-19, as well as an increase in the post-pandemic chronic disease burden. Also, safety (e.g., physical examination effectiveness) and equity issues (e.g., insufficient proactive outreach to vulnerable populations) were identified in the remote consultation setting [
      • Hollander J.E.
      • Carr B.G.
      Virtually perfect? Telemedicine for Covid-19.
      ,
      • Kidd M.R.
      Five principles for pandemic preparedness: lessons from the Australian COVID-19 primary care response.
      ]. Thus, there is a need for a patient-centred telemedicine approach to people with chronic diseases, including those with T2D, and treatment options should be suitable for this scenario [
      • Xia Y.
      • Li Q.
      • Li W.
      • Shen H.
      Elevated mortality of chronic diseases during COVID-19 pandemic: a cause for concern?.
      ]. A selection of some online resources about the virtual consultation setting can be found below.

      5. Treatment recommendations stratified by risk

      5.1 Treatment adherence

      Treatment adherence in patients with T2D is extremely important, since improved adherence is associated with better glycaemic control, mortality and hospital admissions [
      • Khunti K.
      • Seidu S.
      • Kunutsor S.
      • Davies M.
      Association between adherence to pharmacotherapy and outcomes in type 2 diabetes: a meta-analysis.
      ]. A meta-analysis of studies evaluating treatment adherence, persistence, and discontinuation of oral antidiabetic drugs reported that adherence was suboptimal with the pooled proportion of adherent patients of 67.9% (59.6%; 76.3%) in a total of 12 studies evaluated. The discontinuation rate in RCTs was 31.8% (17.0%; 46.7%) in a total of 7 studies evaluated and the mean persistence rate was 56.2% (46.1%; 66.3%) in a total of 6 studies evaluated [
      • Iglay K.
      • Cartier S.E.
      • Rosen V.M.
      • Zarotsky V.
      • Rajpathak S.N.
      • Radican L.
      • Tunceli K.
      Meta-analysis of studies examining medication adherence, persistence, and discontinuation of oral antihyperglycemic agents in type 2 diabetes.
      ]. In another systematic review and meta-analysis that included 34 cohort studies involving almost 600,000 patients with T2D receiving oral an antidiabetic drug, 56.9% (49.3%; 64.4%) of patients with T2D were adherent at one year (proportion of days covered or medication possession ratio ≥0.80) and 44.2% (36.4%; 52.1%) at two years [
      • Ogundipe O.
      • Mazidi M.
      • Chin K.L.
      • Gor D.
      • McGovern A.
      • Sahle B.W.
      • Ofori-Asenso R.
      Real-world adherence, persistence, and in-class switching during use of dipeptidyl peptidase-4 inhibitors: a systematic review and meta-analysis involving 594,138 patients with type 2 diabetes.
      ]. A third systematic review and meta-analysis comprising 48 studies showed that adherence was better for sulphonylureas (SUs) and thiazolidinediones when compared with metformin. Patient-oriented outcomes like treatment satisfaction (measured by Diabetes Treatment Satisfaction Questionnaire scores), when correlated with adherence and persistence, have shown to be significantly higher with glucagon-like peptide-1 receptor agonists (GLP-1RA) drugs as compared with placebo or other active comparators (e.g. metformin, insulin) [
      • Yu M.
      • Van Brunt K.
      • Varnado O.J.
      • Boye K.S.
      Patient-reported outcome results in patients with type 2 diabetes treated with once-weekly dulaglutide: data from the AWARD phase III clinical trial programme.
      ,
      • Ahren B.
      • Masmiquel L.
      • Kumar H.
      • Sargin M.
      • Karsbol J.D.
      • Jacobsen S.H.
      • Chow F.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • Piletic M.
      • Rose L.
      • Axelsen M.
      • DeVries J.H.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ]. A study comparing persistence among new antidiabetic drugs showed differences between drug classes, favoring dipeptidyl peptidase-4 inhibitors (DPP-4is) vs. sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and GLP-1RAs [
      • Jermendy G.
      • Kiss Z.
      • Rokszin G.
      • Abonyi-Toth Z.
      • Wittmann I.
      • Kempler P.
      Persistence to treatment with novel antidiabetic drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists) in people with type 2 diabetes: a nationwide cohort study.
      ]. Schlesinger and colleagues reported in their systematic review and meta-analysis of 19 prospective studies that adhering to a healthy lifestyle (such as mostly favourable diet, physical activity, non-smoking, moderate alcohol intake, and normal weight) reduced the risk of T2D by 78% (14 studies evaluated) and of mortality by 57% (5 studies evaluated) when compared with low adherence to a healthy lifestyle. A reduction in the risk for T2D by 32% (28%; 36%) and for mortality by 21% (15%; 26%) can be attributed to the adherence to every additional healthy lifestyle factor [
      • Schlesinger S.
      • Neuenschwander M.
      • Ballon A.
      • Nothlings U.
      • Barbaresko J.
      Adherence to healthy lifestyles and incidence of diabetes and mortality among individuals with diabetes: a systematic review and meta-analysis of prospective studies.
      ]. In their meta-analysis study, Khunti et al. found that individuals with good adherence had a significant 10% lower rate of hospitalisation events and a significant 28% lower rate of all-cause mortality when compared with a group with poor adherence [
      • Khunti K.
      • Seidu S.
      • Kunutsor S.
      • Davies M.
      Association between adherence to pharmacotherapy and outcomes in type 2 diabetes: a meta-analysis.
      ]. Another study by Anderson et al. showed that patient drug preferences are guided by factors of convenience rather than effectiveness and safety. The study results showed the relative importance for the attributes in rank order as follows: dosing frequency’ (41.6%), ‘type of delivery system (35.5%), ‘frequency of nausea’ (10.4%), ‘weight change’ (5.9%), ‘HbA1c change’ (3.6%), and ‘frequency of hypoglycemia’ (3.0%) [
      • Anderson J.E.
      • Thieu V.T.
      • Boye K.S.
      • Hietpas R.T.
      • Garcia-Perez L.E.
      Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers.
      ].

      5.2 Lifestyle modifications

      As part of their first-line therapy, all patients with T2D should be offered individualised and comprehensive lifestyle counselling including weight management, physical activity, dietary guidance, and smoking cessation. All glycaemic and lifestyle goals should be co-developed and agreed to by the patient and physician. For patients who find it challenging to meet their glycaemic goals, therapeutic lifestyle modifications and adherence to these measures should be discussed at ongoing follow-up visits every 3–6 months. Self-management education and support are pivotal to help patients achieving good results in diabetes control [
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • Piletic M.
      • Rose L.
      • Axelsen M.
      • DeVries J.H.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • A. American Diabetes
      5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes-2021.
      ,
      • Zhang Y.
      • Pan X.F.
      • Chen J.
      • Xia L.
      • Cao A.
      • Zhang Y.
      • Pan A.
      Combined lifestyle factors and risk of incident type 2 diabetes and prognosis among individuals with type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies.
      ].

      5.3 Metformin

      In addition to healthy lifestyle management, newly diagnosed patients with T2D should also be treated with metformin at diabetes diagnosis as the first-line pharmacological therapy of choice. A systematic review and meta-analysis published in 2021 reported that longer-acting metformin (i.e., extended-release and delayed-release formulations) were equally efficient for glycaemic control when compared to the immediate-release formulation, but delayed-release metformin was strongly associated with reduced gastrointestinal effects, and extended-release metformin was associated with reduced serum low-density lipoprotein (LDL) cholesterol concentrations [
      • Tarry-Adkins J.L.
      • Grant I.D.
      • Ozanne S.E.
      • Reynolds R.M.
      • Aiken C.E.
      Efficacy and side effect profile of different formulations of metformin: a systematic review and meta-analysis.
      ]. Clinicians have over 60 years of experience using metformin [
      • Marshall S.M.
      60 years of metformin use: a glance at the past and a look to the future.
      ], thus its risks and benefits are well understood. Metformin is a cost-effective option for glucose lowering, associated with weight loss and fewer hypoglycaemic episodes when compared to insulin or SUs [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • U.K.P.D.S. Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ]. Some evidence suggests it has cardiovascular benefit with respect to myocardial infarction (MI) [
      • A. American Diabetes
      5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes-2021.
      ,

      N. Scottish Intercollegiate Guidelines, Pharmacological Management of Glycaemic Control in People with Type 2 Diabetes, in, 2017.

      ], but the paucity of data from long-term CVOTs creates uncertainty around the effect of metformin in reducing CVD in patients with T2D [
      • Griffin S.J.
      • Leaver J.K.
      • Irving G.J.
      Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes.
      ]. Importantly, metformin has been shown to be associated with gastrointestinal side effects, affecting nearly 25% of patients, among whom 5% develop complete intolerance [
      • Kirpichnikov D.
      • McFarlane S.I.
      • Sowers J.R.
      Metformin: an update.
      ]. Women and elderly were more likely to be intolerant to metformin [
      • Anderson J.E.
      • Thieu V.T.
      • Boye K.S.
      • Hietpas R.T.
      • Garcia-Perez L.E.
      Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers.
      ]. These side effects can often be successfully mitigated in many patients with careful dose titration [
      • Tang Y.
      • Weiss T.
      • Liu J.
      • Rajpathak S.
      • Khunti K.
      Metformin adherence and discontinuation among patients with type 2 diabetes: a retrospective cohort study.
      ].
      Evidence is emerging to support the initiation of a second therapeutic agent along with metformin, rather than waiting for treatment failure with metformin before intensification [
      • Matthews D.R.
      • Paldánius P.M.
      • Proot P.
      • Chiang Y.
      • Stumvoll M.
      • Prato S.D.
      Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial.
      ,
      • Abdul-Ghani M.A.
      • Puckett C.
      • Triplitt C.
      • Maggs D.
      • Adams J.
      • Cersosimo E.
      • DeFronzo R.A.
      Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial.
      ,
      • Garber A.J.
      • Abrahamson M.J.
      • Barzilay J.I.
      • Blonde L.
      • Bloomgarden Z.T.
      • Bush M.A.
      • Umpierrez G.E.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm — 2019 executive summary.
      ]. A Cochrane systematic review published in 2020 evaluated 18 RCTs involving more than 10,000 patients in multiple study arms. Approximately 58% of patients finished the trials in all groups, and the treatment duration varied from one to 10.7 years. The systematic review concluded that metformin monotherapy versus other glucose-lowering drugs, no intervention, or behaviour changing interventions had no apparent influence on the main outcomes of interest such as all-cause mortality, CV mortality, health-related quality of life, serious adverse events, non-fatal MI, non-fatal stroke, and end-stage renal disease (ESRD) [
      • Gnesin F.
      • Thuesen A.C.B.
      • Kahler L.K.A.
      • Madsbad S.
      • Hemmingsen B.
      Metformin monotherapy for adults with type 2 diabetes mellitus.
      ]. These data are supported by evidence of ‘glycaemic legacy’, whereby reduced risk of complications is seen in some studies where patients are treated intensively early in their disease progression, even if this stringent glycaemic control is eventually relaxed [
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Matthews D.R.
      • Neil H.A.W.
      10-year follow-up of intensive glucose control in type 2 diabetes.
      ,
      • Laiteerapong N.
      • Ham S.A.
      • Gao Y.
      • Moffet H.H.
      • Liu J.Y.
      • Huang E.S.
      • Karter A.J.
      The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (The Diabetes & Aging Study).
      ]. It should be noted, however, that evidence for this glycaemic legacy effect is not supported by all follow-up studies [
      • Reaven P.D.
      • Emanuele N.V.
      • Wiitala W.L.
      • Bahn G.D.
      • Reda D.J.
      • McCarren M.
      • Hayward R.A.
      Intensive glucose control in patients with type 2 diabetes — 15-year follow-up.
      ]. To avoid therapeutic inertia, dual therapy may be considered three months after starting metformin treatment in patients who are likely to benefit from better glycaemic control, particularly those with a high baseline HbA1c. The decision of whether to initiate dual therapy should consider individual patient characteristics and treatment goals. If a dual therapy approach is used, patients with cardiovascular or renal disease could gain the benefits of agents shown to reduce risk of cardiovascular events or improve renal parameters (outlined below) earlier in their treatment progression. If metformin monotherapy is chosen at diagnosis, patients should be monitored closely and treatment should be intensified three months after starting metformin, if individualised glycaemic targets are not met and to avoid therapeutic inertia [
      • Goudswaard A.N.
      • Stolk R.P.
      • de Valk H.W.
      • Rutten G.E.H.M.
      Improving glycaemic control in patients with Type 2 diabetes mellitus without insulin therapy.
      ]. For patients on dual therapy who are not meeting treatment goals, additional intensification should be strongly considered to better glycaemic control and avoid therapeutic inertia.

      5.4 Assessing risk in patients with T2D

      CVD represents one of the most prevalent comorbidities of T2D [
      • Sun H.
      • Saeedi P.
      • Karuranga S.
      • Pinkepank M.
      • Ogurtsova K.
      • Duncan B.B.
      • Mbanya J.C.
      IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.
      ], affecting nearly one-third of all patients globally [
      • Einarson T.R.
      • Acs A.
      • Ludwig C.
      • Panton U.H.
      Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017.
      ]. The World Health Organization defines CVD as a group of conditions related to the heart and blood vessels, including coronary heart disease, cerebrovascular disease, and peripheral arterial disease [

      O. World Health, Cardiovascular diseases (CVDs), in, 2017.

      ].
      Understanding the intricate pathophysiological link between CVD and T2D is useful for clinicians when choosing the most suitable and effective treatment for their patients. The physiological mechanisms driving diabetic cardiomyopathy can be used to explain the profound impact of T2D on the cardiovascular system. Most people with T2D have hyperglycaemia, hyperlipidaemia, hypertension, and overweight, all of which confer substantial CVD risk. Diabetes guidelines and intervention strategies therefore mandate an intensified treatment approach to reduce the risk for diabetes-related complications [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Khunti K.
      • Kosiborod M.
      • Ray K.K.
      Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: Time to overcome multifactorial therapeutic inertia?.
      ].
      Awareness and knowledge of all cardiovascular risk factors are critical in determining CVD risk. When primary prevention strategies fail due to pervasive or unmodifiable risk factors, secondary prevention efforts become important, with focus on early detection to preserve quality of life of the patient [
      • Karunathilake S.P.
      • Ganegoda G.U.
      Secondary prevention of cardiovascular diseases and application of technology for early diagnosis.
      ].
      We propose here a pragmatic, evidence-based cardiovascular risk stratification tool intended to complement the tool provided by the American College of Cardiology (ACC)/American Heart Association (AHA) and endorsed by the American Diabetes Association (ADA) [
      • Lloyd-Jones D.M.
      • Braun L.T.
      • Ndumele C.E.
      • Smith S.C.
      • Sperling L.S.
      • Virani S.S.
      • Blumenthal R.S.
      Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: a special report from the American Heart Association and American College of Cardiology.
      ,
      • A. American Diabetes
      10. Cardiovascular disease and risk management: standards of medical care in diabetes-2021.
      ], and guide primary care physicians in their choice for the treatment of patients with T2D (Box 2).

      6. Rationale for risk stratification criteria

      History of established CVD is one of the most widely recognised and important predictors of future major adverse cardiovascular events (MACE) [
      • Young J.B.
      • Gauthier-Loiselle M.
      • Bailey R.A.
      • Manceur A.M.
      • Lefebvre P.
      • Greenberg M.
      • Wysham C.H.
      Development of predictive risk models for major adverse cardiovascular events among patients with type 2 diabetes mellitus using health insurance claims data.
      ]. Similarly, both decreased estimated glomerular filtration rate (eGFR) and albuminuria are strong independent predictors of MACE in patients with T2D [
      • Currie C.J.
      • Berni E.R.
      • Berni T.R.
      • Jenkins-Jones S.
      • Sinsakul M.
      • Jermutus L.
      • Jain M.
      Major adverse cardiovascular events in people with chronic kidney disease in relation to disease severity and diabetes status.
      ]. Finally, there is evidence to suggest that early-onset T2D represents an aggressive form of the disease in terms of cardiovascular risk [
      • Ke C.
      • Shah B.R.
      • Luk A.O.
      • Ruggiero E.D.
      • Chan J.C.N.
      Cardiovascular outcomes trials in type 2 diabetes: time to include young adults, Diabetes.
      ], reflected in the fact that patients with a younger age at diagnosis have a much higher cardiovascular risk than that of age-matched controls [
      • Hillier T.A.
      • Pedula K.L.
      Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth.
      ]. Thus, patients with any of these characteristics are considered to be at very high cardiovascular risk.
      Since T2D itself is considered a major risk factor for CVD, the remaining patients who do not fit these criteria are considered to be at high cardiovascular risk.

      6.1 Patients at very high cardiovascular risk

      The relationship between glucose lowering and CVD in diabetes has been investigated [
      • Yun J.S.
      • Ko S.H.
      Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes.
      ]. The ACCORD trial demonstrated that intensive glucose lowering therapy alone did not translate into a statistically significant or clinically relevant reduction in adverse cardiovascular outcomes. Results from this study suggested a lesser benefit in the first occurrence of nonfatal MI, nonfatal stroke, or death from cardiovascular causes in patients who had previously experienced a cardiovascular event [
      • G. The Action to Control Cardiovascular Risk in Diabetes Study
      Effects of intensive glucose lowering in type 2 diabetes.
      ]. Although some studies observed that intensification of antidiabetic treatment increased the risk of CV events in patients with diabetes (many of them treated with insulin), more recent studies demonstrated an association between the reduction of HbA1c and the decrease in the incidence of CV events (potentially due to the use of drugs that cause less hypoglycaemia) [
      • Boussageon R.
      • Bejan-Angoulvant T.
      • Saadatian-Elahi M.
      • Lafont S.
      • Bergeonneau C.
      • Kassaï B.
      • Cornu C.
      Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.
      ,
      • Zhang H.
      • Qin L.
      • Sheng C.S.
      • Niu Y.
      • Gu H.
      • Lu S.
      • Su Q.
      ASCVD risk stratification modifies the effect of HbA1c on cardiovascular events among patients with type 2 diabetes mellitus with basic to moderate risk.
      ,
      • Rados D.V.
      • Viecceli C.
      • Pinto L.C.
      • Gerchman F.
      • Leitao C.B.
      • Gross J.L.
      Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials.
      ,
      • Huang C.J.
      • Wang W.T.
      • Sung S.H.
      • Chen C.H.
      • Lip G.Y.H.
      • Cheng H.M.
      • Chiang C.E.
      Blood glucose reduction by diabetic drugs with minimal hypoglycaemia risk for cardiovascular outcomes: evidence from meta-regression analysis of randomized controlled trials.
      ,
      • Giugliano D.
      • Chiodini P.
      • Maiorino M.I.
      • Bellastella G.
      • Esposito K.
      Cardiovascular outcome trials and major cardiovascular events: does glucose matter? A systematic review with meta-analysis.
      ,
      • Ambrosi P.
      • Daumas A.
      • Villani P.
      • Giorgi R.
      Glycosylated hemoglobin as a surrogate for the prevention of cardiovascular events in cardiovascular outcome trials comparing new antidiabetic drugs to placebo.
      ,
      • Cavero-Redondo I.
      • Peleteiro B.
      • Alvarez-Bueno C.
      • Rodriguez-Artalejo F.
      • Martinez-Vizcaino V.
      Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis.
      ]. Episodes of severe hypoglycaemia, which can sometimes occur as a consequence of stringent glycaemic targets, are a strong predictor of adverse cardiovascular events and mortality [
      • Hanefeld M.
      • Frier B.M.
      • Pistrosch F.
      Hypoglycemia and cardiovascular risk: is there a major link?.
      ]. However, other meta-analyses and long-term follow-ups do suggest a modest risk reduction for certain macrovascular events for patients treated using long-term intensive glucose-lowering strategies [
      • Tang Y.
      • Weiss T.
      • Liu J.
      • Rajpathak S.
      • Khunti K.
      Metformin adherence and discontinuation among patients with type 2 diabetes: a retrospective cohort study.
      ,
      • Turnbull F.M.
      • Abraira C.
      • Anderson R.J.
      • Byington R.P.
      • Chalmers J.P.
      • Duckworth W.C.
      • Woodward M.
      Intensive glucose control and macrovascular outcomes in type 2 diabetes.
      ,
      • Ray K.K.
      • Seshasai S.R.K.
      • Wijesuriya S.
      • Sivakumaran R.
      • Nethercott S.
      • Preiss D.
      • Sattar N.
      Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
      ]. An epidemiological study based on the Swedish National Diabetes Register supports that glucose control is valuable to reduce the risk of macrovascular complication (i.e., MI and stroke) [
      • Rawshani A.
      • Rawshani A.
      • Franzen S.
      • Sattar N.
      • Eliasson B.
      • Svensson A.M.
      • Gudbjornsdottir S.
      Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.
      ].
      Given these conflicting results, patients at very high cardiovascular risk, and particularly those prone to hypoglycaemia, may benefit from a treatment regimen that balances moderate glycaemic targets with use of agents with proven benefits to cardiovascular risk and renal parameters, as outlined below. A summary of outcome trials and their results examining the cardiovascular and renal effects of various anti-glycaemic treatments is shown in Table 2.
      Table 2Summary of outcome trials.
      Chemical substanceOutcome TrialComparatorPopulationPrior CVDMedian follow upPrimary composite endpointPrimary endpoint HR (95% CI) p-valueAll-cause mortality HR (95% CI) p-valueNumber needed to treat to prevent 1 event
      GLP-1RAs
      LixisenatideELIXA Evaluation of LIXisenatide in Acute coronary syndromePlacebo6,068100%25 months4-point MACE1.02 (0.89; 1.17)

      p<0.001 for non-inferiority; p = 0.81 for superiority [
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • Tardif J.-C.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ]
      0.94 (0.78; 1.13) p = 0.50-
      ExenatideEXSCEL EXenatide Study of Cardiovascular Event LoweringPlacebo14,75273%3.2 years3-point MACE0.91 (0.83; 1.00) p<0.001 for non-inferiority; p = 0.06 for superiority [
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • Thompson V.P.
      • Lokhnygina Y.
      • Buse J.B.
      • Hernandez A.F.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ]
      0.86 (0.77; 0.97) p = 0.016-
      LiraglutideLEADER Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes ResultsPlacebo9,34081%3.8 years3-point MACE0.87 (0.78; 0.97)

      p<0.001 for non-inferiority

      p = 0.01 for superiority [
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.E.
      • Nauck M.A.
      • Buse J.B.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ]
      0.85 (0.74; 0.97)

      p = 0.02
      Primary outcome (over 3 years): 66

      Death from any cause (over 3 years): 98
      SemaglutideSUSTAIN-6 Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 DiabetesPlacebo3,29783%2.1 years3-point MACE0.74 (0.58; 0.95)

      p<0.001 for non-inferiority; p = 0.02 for superiority [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jódar E.
      • Leiter L.A.
      • Vilsbøll T.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]
      1.05 (0.74; 1.50) p = 0.79Primary outcome (over 24 months): 45

      Risk of major CV event (over 3 years): 31 [
      • Anderson S.L.
      • Marrs J.C.
      Antihyperglycemic medications and cardiovascular risk reduction.
      ]
      Oral semaglutidePIONEER 6 Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 DiabetesPlacebo3,18384.6%15.9 months3-point MACE0.79 (0.57; 1.11) p<0.001 for non-inferiority; p = 0.17 for superiority [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • Dungan K.
      • Eliaschewitz F.G.
      • Franco D.R.
      • Bain S.C.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]
      0.51 (0.31; 0.84) no p-value reported-
      AlbiglutideHARMONY Outcomes Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular diseasePlacebo9,463100%1.5 years3-point MACE0.78 (0.68; 0.90) p<0.0001 for non-inferiority; p = 0.0006 for superiority [
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D’Agostino R.B.
      • Granger C.B.
      • Jones N.P.
      • Mandal T.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ]
      0.95 (0.79; 1.16) p = 0.644Primary event outcome (over 1.6 years): 50
      DulaglutideREWIND Researching Cardiovascular Events with a Weekly Incretin in DiabetesPlacebo9,90131%5.4 years3-point MACE0.88 (0.79; 0.99) p = 0.026 for superiority [
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • Diaz R.
      • Lakshmanan M.
      • Pais P.
      • Zigrang W.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ]
      0.90 (0.80; 1.01) p = 0.067For people with a previous CV event (over 5 years): 18
      SGLT-2i
      EmpagliflozinEMPA-REG OUTCOME Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 DiabetesPlacebo7,02099%3.1 years3-point MACE0.86 (0.74; 0.99) p<0.001 for non-inferiority;

      p = 0.04 for superiority [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • Inzucchi S.E.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ]
      0.68 (0.57; 0.82) p <0.001Risk of MACE (over 3.1 years): 63 [
      • Cefalu W.T.
      • Kaul S.
      • Gerstein H.C.
      • Holman R.R.
      • Zinman B.
      • Skyler J.S.
      • Riddle M.C.
      Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors’ expert forum.
      ]

      Risk of death from any cause (over 3 years): 39
      EmpagliflozinEMPEROR-Reduced

      Empagliflozin Outcome

      Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction
      Placebo3,730100%16 monthsCV death/

      HHF
      0.76 (0.67; 0.87) p<0.0001 [
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Pocock S.J.
      • Zannad F.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial.
      ]
      0.92 (0.77 to 1.10) No p-value reported [
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • E.M.-R.T. Investigators
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ]
      Primary outcome: 19 [
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Pocock S.J.
      • Carson P.
      • E.M.-R.T. Investigators
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ]
      CanagliflozinCANVAS Canagliflozin Cardiovascular Assessment StudyPlacebo10,14266%126.1 weeks3-point MACE0.86 (0.75; 0.97) p<0.001 for non-inferiority;

      p = 0.02 for superiority [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • Matthews D.R.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ]
      0.87 (0.74; 1.01) p = 0.24 for superiorityAdditional major CV event (over 3 years): 179 [
      • Anderson S.L.
      • Marrs J.C.
      Antihyperglycemic medications and cardiovascular risk reduction.
      ]
      CanagliflozinCREDENCE

      Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation
      Placebo4,40150.4%2.62 yearsESKD, doubling of serum creatinine, or renal or CV death0.70 (0.59; 0.82); p = 0.00001

      [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • Mahaffey K.W.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]
      0.83 (0.68; 1.02) no p-value reportedPrimary outcome: 22 (15; 38)

      Composite outcome of ESKD, doubling of serum creatinine, or renal death (over 2.62 years): 28

      ESKD events (over 2.62 years): 43

      HHF: 45

      Composite events of CV death, MI, or stroke (over 2.62 years): 40
      DapagliflozinDECLARE-TIMI 58 Dapagliflozin Effect on Cardiovascular Events –Thrombolysis in Myocardial Infarction 58Placebo17,16041%4.2 years3-point MACE0.93 (0.84; 1.03) p = 0.17 for superiority [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Sabatine M.S.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ]
      0.93 (0.82; 1.04) No p-value reportedCV death or HHF in patients with prior MI (over a period of 4 years): 53 [
      • Cefalu W.T.
      • Kaul S.
      • Gerstein H.C.
      • Holman R.R.
      • Zinman B.
      • Skyler J.S.
      • Riddle M.C.
      Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors’ expert forum.
      ]
      DapagliflozinDAPA-HF

      Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure)
      Placebo4,744100%18.2 monthsWorsening HF or death from CV causes0.74 (0.65; 0.85) p<0.001 for superiority [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Køber L.
      • Kosiborod M.N.
      • Martinez F.A.
      • Langkilde A.-M.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]
      0.83 (0.71; 0.97) No p-value reportedPrimary outcome: 21
      DapagliflozinDAPA-CKD Dapagliflozin and Prevention

      of Adverse Outcomes in Chronic Kidney

      Disease
      Placebo4,30437.4%2.4 yearsSustained decline in

      the eGFR of at least 50%, end-stage kidney disease, or death from renal

      or CV causes
      0.61 (0.51; 0.72) p<0.001 [
      • Heerspink H.J.L.
      • Stefansson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • Investigators
      Dapagliflozin in patients with chronic kidney disease.
      ]
      0.69 (0.53; 0.88) p = 0.004Primary outcome: 19
      ErtugliflozinVERTIS CV Evaluation of Ertugliflozin Efficacy

      and Safety Cardiovascular Outcomes Trial
      Placebo8,246100%3.5 years3-point MACE0.97 (0.85; 1.11) p<0.001 for noninferiority [
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • Investigators V.C.
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ]
      0.93 (0.80; 1.08) No p-value reported-
      SotagliflozinSOLOIST-WHF Effect of Sotagliflozin on Cardiovascular Events

      in Patients with Type 2 Diabetes Post Worsening

      Heart Failure
      Placebo1,222100%9.2 monthsTotal number of CV deaths, hospitalisations, and urgent visits for HF (first and subsequent events)067 (0.52; 0.85) p<0.001 [
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • S.-W.T. Investigators
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      ]
      0.82 (0.59; 1.14) No p-value reported-
      SotagliflozinSCORED Effect of Sotagliflozin on Cardiovascular and Renal

      Events in Patients with Type 2 Diabetes and

      Moderate Renal Impairment Who Are at Cardiovascular

      Risk
      Placebo10,58431%16.0 monthsTotal number of CV deaths,

      hospitalisations for HF, and urgent visits for HF
      HR: 0.74 (0.63; 0.88) p<0.001 [
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • Kosiborod M.N.
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ]
      0.99 (0.83; 1.18) No p-value reported-
      DPP-4i
      AlogliptinEXAMINE Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of CarePlacebo5,380100%18 months3-point MACE0.96 (≤1.16)

      p<0.001 for non-inferiority; p = 0.32 for superiority [
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • Zannad F.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      ]
      0.88 (0.71; 1.09) p = 0.23
      SaxagliptinSAVOR-TIMI 53 Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial InfarctionPlacebo16,49290.9%2.1 years3-point MACE1.00 (0.89; 1.12) p = 0.99 for superiority; p<0.001 for non-inferiority [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • Raz I.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ]
      1.11 (0.96; 1.27) p = 0.15-
      LinagliptinCARMELINA CArdiovascular safety and Renal Microvascular OutcomE with Linagliptin in Patients With Type 2 DiabetesPlacebo7,00357%2.2 years3-point MACE1.02 (0.89; 1.17)

      p<0.001 for non-inferiority; p = 0.74 for superiority

      [
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • McGuire D.K.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA Randomized Clinical Trial.
      ]
      0.98 (0.84; 1.13) p = 0.74-
      LinagliptinCAROLINA CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in Patients with Type 2 DiabetesGlimepiride6,03335%6.3 years3-point MACE0.98 (0.84; 1.14) p<0.0001 for non-inferiority; p = 0.76 for superiority [
      • Rosenstock J.
      • Kahn S.E.
      • Johansen O.E.
      • Zinman B.
      • Espeland M.A.
      • Woerle H.J.
      • Marx N.
      Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA Randomized Clinical Trial.
      ]
      0.91 (0.78; 1.06) p-value not significant-
      Insulin
      Insulin degludecDEVOTE

      Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events
      Insulin glargine U1007,63785.2%1.83 years3-point MACE0.91 (0.78; 1.06) p<0.001 for noninferiority [
      • Marso S.P.
      • McGuire D.K.
      • Zinman B.
      • Poulter N.R.
      • Emerson S.S.
      • Pieber T.R.
      • Buse J.B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      ]
      0.91 (0.76; 1.11)

      p = 0.35
      -
      CV, cardiovascular; ESKD, end-stage kidney disease; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular event; MI, myocardial infarction.

      6.2 Patients with atherosclerotic cardiovascular disease (ASCVD)

      ASCVD is the primary cause of morbidity and mortality in individuals with T2D [
      • A. American Diabetes
      10. Cardiovascular disease and risk management: standards of medical care in diabetes—2019.
      ]. ASCVD is broadly defined as atherosclerosis leading to coronary artery disease, cerebrovascular disease, or peripheral arterial disease [
      • A. American Diabetes
      10. Cardiovascular disease and risk management: standards of medical care in diabetes—2019.
      ]. While differences exist in how ASCVD is reported across clinical trials, all CVOTs have enrolled some proportion of patients with established CVD (prior MI, stroke, or arterial revascularisation), and a range of patients with clinically significant atherosclerosis (prior transient ischaemic attack, hospitalised unstable angina, amputation, congestive heart failure [HF] New York Heart Association class II–III, >50% stenosis of any artery, symptomatic or asymptomatic coronary artery disease documented by imaging, CKD with eGFR <60 mL/min/1.73 m2) [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ].
      When deciding on the most appropriate and effective antidiabetic medication to add after or with metformin, it is important to consider the presence of other diabetes-associated comorbidities. The presence of ASCVD in people with T2D strongly advocates choosing a glucose-lowering therapy that not only reduces HbA1c but also controls and prevents worsening of ASCVD, hospitalisation for HF, renal disease, and mortality. Therapy in patients at increased risk of stroke should also be focused on lowering blood pressure, which has been shown to dramatically lower the risk [
      • Lawes Carlene M.M.
      • Bennett Derrick A.
      • Feigin Valery L.
      • Rodgers A.
      Blood pressure and stroke.
      ].

      6.2.1 Glucagon-like peptide-1 receptor agonists

      There is substantial evidence from large CVOTs corroborating the use of some GLP-1RAs in patients with T2D and established ASCVD. GLP-1RAs are recommended for initial intensification. Among the list of trials that investigated this drug class, the LEADER trial demonstrated superiority of liraglutide compared to placebo in reducing the risk of death from cardiovascular causes, nonfatal (including silent) MI, or nonfatal stroke [HR: 0.87 (0.78; 0.97), Number needed to treat (NNT): 66–67 over 3 years] [
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.E.
      • Nauck M.A.
      • Buse J.B.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ]. In the SUSTAIN 6 trial that compared the injectable GLP-1RA semaglutide to placebo, the rate of cardiovascular death, nonfatal MI, or nonfatal stroke was 26% lower among patients receiving semaglutide than among those receiving placebo [HR: 0.74 (0.58; 0.95), NNT: 45 over 24 months]. Based on the design of the study, this result reflects noninferiority of semaglutide compared to placebo. Semaglutide had a neutral effect on the number and rate of occurrence of severe hypoglycaemic episodes [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jódar E.
      • Leiter L.A.
      • Vilsbøll T.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. The oral formulation of semaglutide also demonstrated noninferiority to placebo in the PIONEER 6 trial, achieving its primary objective of no excess cardiovascular risk [HR: 0.79 (0.57; 1.11)] [
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • Dungan K.
      • Eliaschewitz F.G.
      • Franco D.R.
      • Bain S.C.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. Although the overall number of retinopathy events was low, there was an unexpected higher rate of retinopathy complications (vitreous haemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) in the semaglutide group in both studies [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jódar E.
      • Leiter L.A.
      • Vilsbøll T.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • Dungan K.
      • Eliaschewitz F.G.
      • Franco D.R.
      • Bain S.C.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. Most cases were non-proliferative, were identified during routine examination, and resulted in no new treatment. In addition, the increase was observed only in patients with previous retinopathy and in patients with the greatest and most rapid reduction in HbA1c, similar to effects seen with insulin and in patients with type 1 diabetes [
      • Dahl-Jørgensen K.
      • Brinchmann-Hansen O.
      • Hanssen K.F.
      • Sandvik L.
      • Aagenaes O.
      Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study.
      ].
      To further add to the repertoire of CVOTs in patients with T2D and established CVD, the Harmony Outcomes trial confirmed albiglutide (not commercially available) was superior to placebo in reducing MACE [HR: 0.78 (0.68; 0.90), NNT: 50 over 1.6 years] [
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D’Agostino R.B.
      • Granger C.B.
      • Jones N.P.
      • Mandal T.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ]. More recently, results from the REWIND trial showed the addition of dulaglutide to existing diabetes treatment reduced the primary composite of cardiovascular outcomes over 5 years in a broad range of people with T2D [HR: 0.88 (0.79; 0.99), NNT for patients with a prior cardiovascular event: 18 over 5 years]. REWIND differed from preceding CVOTs with GLP-1RAs in that only 31% of participants had established CVD. Of note, in the REWIND trial, the risk of eye outcomes was numerically higher with dulaglutide compared with the placebo group [
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • Diaz R.
      • Lakshmanan M.
      • Pais P.
      • Zigrang W.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ].
      Despite the well-recognised benefit of GLP-1RAs in effectively altering the rate of MACE, it is also important to address that some drugs of this class have not been shown to significantly improve cardiovascular outcomes. Neither lixisenatide [HR: 1.02 (0.89; 1.17)] nor exenatide [HR: 0.91 (0.83; 1.00)] showed significant improvements in risk of MACE [
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • Tardif J.-C.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • Thompson V.P.
      • Lokhnygina Y.
      • Buse J.B.
      • Hernandez A.F.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ]. Overall, a recent systematic review of GLP-1RA CVOTs identified a class effect for risk reduction of MACE, cardiovascular mortality, and all-cause death [
      • Bethel M.A.
      • Patel R.A.
      • Merrill P.
      • Lokhnygina Y.
      • Buse J.B.
      • Mentz R.J.
      • E.S. Group
      Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis.
      ]. Patients and HCPs should also discuss the considerable inter-individual variation in magnitude of effect on HbA1c and weight loss in patients treated with GLP-1RAs, and continued treatment with these therapies should be evaluated after 6 months.

      6.2.2 Sodium-glucose co-transporter-2 inhibitors

      Among the SGLT-2is, empagliflozin and canagliflozin have demonstrated beneficial effects in reducing MACE in patients with T2D and ASCVD. Almost all patients included in the EMPA-REG OUTCOME trial had previous CVD, and treatment with empagliflozin was shown to reduce risk of the primary MACE endpoint by 14% compared to placebo [HR: 0.86 (0.74; 0.99), NNT: 63 over 3.1 years]. While this trial showed no significant differences in the rates of MI or stroke when treated with empagliflozin, this treatment did lead to significant reductions in rates of death from cardiovascular causes, hospitalisation for HF, and death from any cause [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • Inzucchi S.E.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ]. Results from the CANVAS Program, which included a broad patient population of whom more than 65% had a history of CVD, confirmed the superiority of canagliflozin compared with placebo in significantly lowering the rate of the primary outcome, which was a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke [HR: 0.87 (0.75; 0.97), NNT for patients with a prior cardiovascular event: 179 over 3 years] [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • Matthews D.R.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ]. More recently, the DECLARE-TIMI 58 study (with ∼40% of patients with established CVD) did not demonstrate significantly decreased risk of MACE for dapagliflozin compared to placebo [HR: 0.93 (0.82; 1.04)], but did result in decreased rates of cardiovascular death or hospitalisation for HF [HR 0.83 (0.73; 0.95), NNT: 53 over 4 years] [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Sabatine M.S.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ]. These results were corroborated by a subsequent meta-analysis that confirmed moderate benefits of SGLT-2is on atherosclerotic events in patients with established CVD [
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Bonaca M.P.
      • Sabatine M.S.
      SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      ]. In the CVOT VERTIS trial, the fourth SGLT-2i, ertugliflozin, was non-inferior to placebo for reducing cardiovascular events in patients with T2D and established CVD. There seems to be a consistent chemical subgroup effect regarding reductions in HF hospitalisations [HR: 0.70 (0.54; 090)], but reductions in major adverse cardiac events were only statistically significant for canagliflozin and empagliflozin [
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • Investigators V.C.
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ].

      6.2.3 Insulin

      Importantly, insulin should only be used in patients with T2D and ASCVD when other options have been attempted and co-developed glycaemic goals have not been met. Apart from the DEVOTE trial, which demonstrated non-inferiority of insulin degludec to insulin glargine U100 on cardiovascular outcomes [
      • Marso S.P.
      • McGuire D.K.
      • Zinman B.
      • Poulter N.R.
      • Emerson S.S.
      • Pieber T.R.
      • Buse J.B.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.
      ], there have been no other trials to date that have investigated the cardiovascular safety of insulin in patients with T2D established CVD. Thus, GLP-1RAs are recommended before insulin as the first injectable treatment by a number of clinical practice guidelines [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • Kernan W.N.
      • Mathieu C.
      • Mingrone G.
      • Buse J.B.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Buse J.B.
      • Wexler D.J.
      • Tsapas A.
      • Rossing P.
      • Mingrone G.
      • Mathieu C.
      • Davies M.J.
      2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • Bailey C.J.
      • Ceriello A.
      • Delgado V.
      • Chowdhury T.A.
      2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      ].
      Ultimately, SGLT-2is (empagliflozin, canagliflozin, and dapagliflozin) and GLP-1RAs (liraglutide, semaglutide, albiglutide, and dulaglutide) have been the only chemical subgroups to show proven CV benefit in patients with T2D and ASCVD, with the exception of ertugliflozin, considering the CVOT VERTIS trial results [
      • Palmer S.C.
      • Tendal B.
      • Mustafa R.A.
      • Vandvik P.O.
      • Li S.
      • Hao Q.
      • Strippoli G.F.M.
      Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.
      ].

      6.3 Patients with HF

      HF is an increasingly common comorbidity associated with T2D, with up to 40% prevalence in patients with T2D and a median patient survival rate of only around 4 years [
      • Llano A.
      • McKay G.
      The treatment of type 2 diabetes in heart failure.
      ,
      • Cubbon R.M.
      • Adams B.
      • Rajwani A.
      • Mercer B.N.
      • Patel P.A.
      • Gherardi G.
      • Kearney M.T.
      Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology.
      ,
      • Lehrke M.
      • Marx N.
      Diabetes mellitus and heart failure.
      ]. Increased risk of HF in patients with T2D has been shown to be associated with greater insulin use and poor glycaemic control [
      • Wang Y.
      • Negishi T.
      • Negishi K.
      • Marwick T.H.
      Prediction of heart failure in patients with type 2 diabetes mellitus- a systematic review and meta-analysis.
      ]. Despite the poor prognosis and high medical demand for effective therapies for patients with diabetes and HF, treatment options remain scarce [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • Matthews D.R.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Lawson C.A.
      • Jones P.W.
      • Teece L.
      • Dunbar S.B.
      • Seferovic P.M.
      • Khunti K.
      • Kadam U.T.
      Association between type 2 diabetes and all-cause hospitalization and mortality in the uk general heart failure population: stratification by diabetic glycemic control and medication intensification.
      ,
      • Lawson C.A.
      • Zaccardi F.
      • Squire I.
      • Ling S.
      • Davies M.J.
      • Lam C.S.P.
      • Kadam U.T.
      20-year trends in cause-specific heart failure outcomes by sex, socioeconomic status, and place of diagnosis: a population-based study.
      ].

      6.3.1 Sodium-glucose co-transporter-2 inhibitors

      There is good evidence supporting the use of SGLT-2is in patients with T2D and heart failure with reduced ejection fraction (HFrEF), with demonstrated favourable effects on cardiovascular outcomes, in addition to reducing hyperglycaemia [
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Hantel S.
      • Salsali A.
      • Inzucchi S.E.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.
      ]. SGLT-2is are now indicated in adults for the treatment of HF with HFrEF in different parts of the world, including Europe [
      • Kosiborod M.
      • Cavender Matthew A.
      • Fu Alex Z.
      • Wilding John P.
      • Khunti K.
      • Holl Reinhard W.
      • Fenici P.
      Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs.
      ,
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • E.M.-P.T. Investigators
      Empagliflozin in heart failure with a preserved ejection fraction.
      ]. The first drugs of this class available for the treatment of T2D that were shown to improve the risk of hospitalisation for HF were empagliflozin and canagliflozin [
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D’Agostino R.B.
      • Granger C.B.
      • Jones N.P.
      • Mandal T.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ,
      • Palmer S.C.
      • Tendal B.
      • Mustafa R.A.
      • Vandvik P.O.
      • Li S.
      • Hao Q.
      • Strippoli G.F.M.
      Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.
      ,
      • Rådholm K.
      • Figtree G.
      • Perkovic V.
      • Solomon S.D.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Neal B.
      Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program.
      ]. Post hoc analyses of data from the EMPA-REG OUTCOME showed that empagliflozin resulted in significant reductions in hospitalisation for HF, as well as in death from cardiovascular causes, for patients with and without HF at baseline [
      • Llano A.
      • McKay G.
      The treatment of type 2 diabetes in heart failure.
      ]. Results from the CANVAS Program suggest that the significant reduction in the risk of hospitalisation for HF with canagliflozin may be greater in patients with prior history of HF compared to those without [
      • Cubbon R.M.
      • Adams B.
      • Rajwani A.
      • Mercer B.N.
      • Patel P.A.
      • Gherardi G.
      • Kearney M.T.
      Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology.
      ]. Furthermore, dapagliflozin was more recently shown to lower the rates of cardiovascular death and hospitalisation for HF in a broad patient population. Although similar reductions were seen in patients regardless of history of ASCVD or HF, only 10% of patients had a history of HF [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Sabatine M.S.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ]. The DAPA-HF study sought to further examine the patient population with established HF and showed benefits in reduced hospitalisation for HF and mortality in patients with HF with and without diabetes. This trial is the first to show benefits specifically in patients with prior HF without diabetes and reinforces the use of these drugs in this population. The primary endpoint of the study, the composite of a first episode of worsening HF or cardiovascular death, occurred in 16.3% in the dapagliflozin group and in 21.2% in the placebo group [HR: 0.74; (0.65; 0.85), NNT: 21]. The results were consistent in the prespecified subgroup of patients with T2D at baseline [HR: 0.75 (0.63; 0.90)] [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • Køber L.
      • Kosiborod M.N.
      • Martinez F.A.
      • Langkilde A.-M.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]. More recently, the EMPEROR-Reduced trial revealed that empagliflozin reduced HF hospitalisations [HR 0.70 (0.63; 0.78)] in patients with HFrEF. The magnitude of the observed benefits was comparable in patients with and without diabetes at enrolment [
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Pocock S.J.
      • Zannad F.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial.
      ]. In the SOLOIST-WHF trial, patients with T2D and recent worsening HF received placebo or sotagliflozin, which is not approved for patients with T2D yet. The rate of the total number of CV deaths, hospitalisations, and urgent visits for HF was 51.0 per 100 patient-years in the sotagliflozin group and 76.3 per 100 patient-years in the placebo group [HR: 067 (0.52; 0.85)]. The authors mentioned that the trial was ended early due to funding loss, which led to a significant reduction in power to test the original primary endpoint [
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • S.-W.T. Investigators
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      ]. The SCORED trial compared sotagliflozin with placebo in reducing CV events in patients with T2D, CKD (eGFR rate, 25–60 mL/min/1.73 m2 of body-surface area), and risks for CV disease. The primary endpoint, a composite of the total number of CV deaths, hospitalisations for HF, and urgent visits for HF, was lower to sotagliflozin when compared to placebo [(5.6 vs. 7.5 events per 100 patient-years; HR: 0.74 (0.63; 0.88)]. The authors indicated that the original co-primary endpoint was the first occurrence of MACE (defined as CV deaths, non-fatal MI, or non-fatal stroke) and the first occurrence of CV deaths or hospitalisation for HF, but it had to be changed due to funding loss [
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • Kosiborod M.N.
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ]. These studies, DAPA-HF, EMPEROR-Reduced, SOLOIST-WHF, and SCORED, confirm the role of SGLT-2i agents for the management of HF or CKD even in patients without diabetes [
      • Lehrke M.
      • Marx N.
      Diabetes mellitus and heart failure.
      ,
      • Wang Y.
      • Negishi T.
      • Negishi K.
      • Marwick T.H.
      Prediction of heart failure in patients with type 2 diabetes mellitus- a systematic review and meta-analysis.
      ,
      • Lawson C.A.
      • Jones P.W.
      • Teece L.
      • Dunbar S.B.
      • Seferovic P.M.
      • Khunti K.
      • Kadam U.T.
      Association between type 2 diabetes and all-cause hospitalization and mortality in the uk general heart failure population: stratification by diabetic glycemic control and medication intensification.
      ,
      • Lawson C.A.
      • Zaccardi F.
      • Squire I.
      • Ling S.
      • Davies M.J.
      • Lam C.S.P.
      • Kadam U.T.
      20-year trends in cause-specific heart failure outcomes by sex, socioeconomic status, and place of diagnosis: a population-based study.
      ]. Also, in patients with HFrEF, the aim should be to up-titrate renin-angiotensin-aldosterone system inhibitors and beta-blockers to the target or maximum-tolerated doses in a timely fashion. Mineralocorticoid receptor antagonists can be added before achieving the maximally tolerated or target doses of the other medications [
      • Committee W.
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • Allen L.A.
      • Breathett K.
      • Butler J.
      • Youmans Q.R.
      2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      ].
      While these clinical trial data examine patients with HFrEF, heart failure with preserved ejection fraction (HFpEF) has been less well studied, despite its common association with T2D. However, the CVD-REAL real-world evidence study showed reduced risk of hospitalisation for any HF and mortality in patients taking SGLT-2is [
      • Kosiborod M.
      • Cavender Matthew A.
      • Fu Alex Z.
      • Wilding John P.
      • Khunti K.
      • Holl Reinhard W.
      • Fenici P.
      Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs.
      ]. Clinical trials examining SGLT-2i treatment specifically in patients with HFpEF indicate that empagliflozin reduced the combined risk of cardiovascular death or hospitalisation for HF in patients with HF and a preserved ejection fraction, regardless of the presence or absence of diabetes [
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Ferreira J.P.
      • Bocchi E.
      • Bohm M.
      • E.M.-P.T. Investigators
      Empagliflozin in heart failure with a preserved ejection fraction.
      ].
      Despite their benefits, patients and physicians should be aware that an increased risk of lower limb amputation was observed in patients treated with canagliflozin in the CANVAS Program, but not in other trials with SGLT-2is, including several observational studies [
      • Scheen A.J.
      Does lower limb amputation concern all SGLT2 inhibitors?.
      ]. A more recent study (CREDENCE) did not observe the increased risk for bone fractures and lower-limb amputations previously reported in CANVAS. Globally, these two studies reinforce a favourable risk-benefit balance of canagliflozin in a T2D population with CV or renal risk [
      • Scheen A.
      Canagliflozine et protection cardio-renale chez le patient diabetique de type 2: de CANVAS a CREDENCE.
      ,
      • Li C.X.
      • Liang S.
      • Gao L.
      • Liu H.
      Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: a real-world systematic review and meta-analysis.
      ]. That said, patients should be cautious of other pre-existing factors that increase fracture risk. Physicians should also encourage proper hygiene in both female and male patients to avoid genital mycotic infections common with this class of drug (and which may affect treatment adherence) [
      • Engelhardt K.
      • Ferguson M.
      • Rosselli J.L.
      Prevention and management of genital mycotic infections in the setting of sodium-glucose cotransporter 2 inhibitors.
      ,
      • I. Janssen Pharmaceuticals
      Invokana (canagliflozin) Prescribing Information.
      ,
      • C. AstraZeneca
      Forxiga (dapagliflozin) [summary of product characteristics].
      ,
      • P. Boehringer Ingelheim
      Jardiance (empagliflozin) Prescribing Information.
      ]. Patients should also be counselled to maintain adequate fluid intake to prevent dehydration and hypotension from increased urination. Physicians should also be aware of the risk of uncommon but severe side effects as diabetic ketoacidosis and the rarer but highly severe Fournier gangrene. A few cases of diabetic ketoacidosis have been reported in patients who had recently undergone major surgery, decreased or discontinued insulin, or were diagnosed with T2D and subsequently found to have latent autoimmune diabetes of adulthood [
      • Burke K.R.
      • Schumacher C.A.
      • Harpe S.E.
      SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature.
      ].

      6.3.2 Thiazolidinediones

      Certain drug families should also be particularly avoided when treating patients with T2D and HF. The PROactive trial demonstrated that the thiazolidinedione pioglitazone (commercial availability varies from country to country) was associated with a 50% increase in hospitalisation for HF compared to patients treated with placebo [
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.A.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • Investigators P.R.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
      ]. A meta-analysis of RCTs studying the effect of pioglitazone in secondary prevention of established CVD showed increased risk of HF despite lowered risk of recurrent MACE, stroke, and MI [
      • de Jong M.
      • van der Worp H.B.
      • van der Graaf Y.
      • Visseren F.L.J.
      • Westerink J.
      Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials.
      ]. Direct comparison trials assessing the incidence of cardiovascular events between pioglitazone and other antidiabetic medications is limited to the TOSCA.IT trial, which compared pioglitazone with SUs (mostly glimepiride and gliclazide) which showed a non-statistically significant but numerically higher risk of HF in patients treated with pioglitazone [
      • Vaccaro O.
      • Masulli M.
      • Nicolucci A.
      • Bonora E.
      • Del Prato S.
      • Maggioni A.P.
      • Agrusta M.
      Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.
      ]. Thus, pioglitazone is not recommended in the treatment of patients with T2D and HF, due to its demonstrated increased risk in HF-associated adverse cardiovascular effects, as well as the inadequacy of robust data from multiple dedicated trials.

      6.3.3 Dipeptidyl peptidase-4 inhibitors

      To date, there are no demonstrated benefits on CV outcomes of DPP-4is, and caution may be warranted when using saxagliptin in T2D patients with HF [
      • Packer M.
      Worsening heart failure during the use of DPP-4 inhibitors.
      ,
      • Liu D.
      • Jin B.
      • Chen W.
      • Yun P.
      Dipeptidyl peptidase 4 (DPP-4) inhibitors and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM): a systematic review and meta-analysis.
      ]. In the SAVOR-TIMI 53 trial, saxagliptin was associated with an increased relative risk of hospitalisation for HF, which was higher among patients with prior HF [
      • Scirica B.M.
      • Braunwald E.
      • Raz I.
      • Cavender M.A.
      • Morrow D.A.
      • Jarolim P.
      • Bhatt D.L.
      Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 Randomized Trial.
      ]. Furthermore, in a post hoc analysis, a small increase in hospitalisation for HF was observed in patients without a history of HF randomised to receive alogliptin in the EXAMINE trial, compared to those assigned to placebo; however, an interaction between treatment and history of HF was not found in the analysis, and there was no statistically significant difference between the two treatment groups in all-cause death and hospitalisation for HF, irrespective of history of HF [
      • Zannad F.
      • Cannon C.P.
      • Cushman W.C.
      • Bakris G.L.
      • Menon V.
      • Perez A.T.
      • White W.B.
      Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.
      ]. The two other CVOTs examining DPP-4is, TECOS examining sitagliptin and CARMELINA evaluating linagliptin, failed to demonstrate any significant difference in the rate of hospitalisation for HF between the DPP-4i and placebo groups [
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • Holman R.R.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      ,
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • McGuire D.K.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA Randomized Clinical Trial.
      ]. The CAROLINA trial sought to further examine the noninferiority of linagliptin compared with glimepiride in preventing CV events. One of the secondary endpoints of the study, hospitalisation for HF, occurred in 3.7% in the linagliptin group and in 3.1% in the glimepiride group [HR: 1.21 (0.92; 1.59)] [
      • Rosenstock J.
      • Kahn S.E.
      • Johansen O.E.
      • Zinman B.
      • Espeland M.A.
      • Woerle H.J.
      • Marx N.
      Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA Randomized Clinical Trial.
      ].

      6.3.4 Insulin

      Insulin treatment has been associated with renal sodium retention and oedema, particularly when used in combination with thiazolidinediones [
      • DeFronzo R.A.
      • Cooke C.R.
      • Andres R.
      • Faloona G.R.
      • Davis P.J.
      The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man.
      ,
      • Raskin P.
      • Rendell M.
      • Riddle M.C.
      • Dole J.F.
      • Freed M.I.
      • Rosenstock J.
      • G. Rosiglitazone Clinical Trials Study
      A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes.
      ]. Assessing whether insulin treatment worsens HF has been difficult, given that patients treated with insulin typically have more advanced T2D and a greater degree of comorbidity and thus, clinical severity. However, a recent meta-analysis showed that insulin treatment in patients with HF was associated with a higher risk of death and hospitalisation for HF, irrespective of diabetes duration [
      • Cosmi F.
      • Shen L.
      • Magnoli M.
      • Abraham W.T.
      • Anand I.S.
      • Cleland J.G.
      • Latini R.
      Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes.
      ]. For those with HF, patients and HCPs should carefully weigh the benefits of stricter glycaemic control against the risks of worsening HF, with reduced insulin intensification given serious consideration.
      In conclusion, SGLT-2is may be beneficial and are recommended for the treatment of patients with T2D and HF. Insulin treatment should be used with caution in patients who develop or have a history of HF. Saxagliptin or pioglitazone should be used only when there are no other therapeutic options available. GLP-1RAs and DPP-4is, other than saxagliptin, have not shown any benefits or harms in the risk for HF in patients with T2D.

      6.3.5 Glucagon-like peptide-1 receptor agonists

      A meta-analysis published in 2020 evaluated the effects of GLP1-RAs on HF, and reported that GLP1-RAs did not increase the HF risk [Mantel-Haenszel odds ratio 0.93 (0.85; 1.01), p = 0.09] with no discrepancy between different groups. Independent comparison between trials with and without cardiovascular endpoints showed that there was no significant between-group difference. No significant trend toward a reduction in HF was observed after adding non-cardiovascular outcomes to the analysis. The authors concluded that GLP1-RAs do not have the same stellar effects as other drug classes, and their effects on HF remain unclear, although they highlighted that one of the limitations of the meta-analysis was that the definition of HF was heterogeneous across trials [
      • Nreu B.
      • Dicembrini I.
      • Tinti F.
      • Sesti G.
      • Mannucci E.
      • Monami M.
      Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials.
      ].

      6.4 Patients with CKD

      Diabetes is the leading cause of CKD, and 25–40% of people with T2D also have CKD [
      • Alicic R.Z.
      • Rooney M.T.
      • Tuttle K.R.
      Diabetic kidney disease: challenges, progress, and possibilities.
      ,
      • Khunti K.
      • Charbonnel B.
      • Chen H.
      • Cherney D.Z.
      • Cooper A.
      • Fenici P.
      • Investigators D.
      Prevalence and progression of chronic kidney disease among patients with type 2 diabetes: insights from the DISCOVER study.
      ]. The kidney microvasculature is particularly sensitive to the damaging effects of hyperglycaemia, leading to impaired renal function [
      • Brownlee M.
      The pathobiology of diabetic complications: a unifying mechanism.
      ]. Importantly, CKD puts limitations on the glucose-lowering therapies that can be used [
      • Davies M.
      • Chatterjee S.
      • Khunti K.
      The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies.
      ], making good glycaemic control increasingly difficult. Although these patients are at very high cardiovascular risk, patients and physicians are encouraged to choose as stringent glycaemic targets as are deemed safe to limit the worsening of microvascular disease [
      • A.D. Association
      11. Microvascular complications and foot care: standards of medical care in diabetes—2019.
      ]. Patients with diabetes with lower eGFR levels had a higher percentage of avoidable deaths and cardiovascular hospitalisations than those with other cardiovascular risk factors [
      • Ruiz-Quintero M.
      • Redon J.
      • Tellez-Plaza M.
      • Cebrian-Cuenca A.M.
      • Navarro-Perez J.
      • Menendez E.
      • Carratala-Munuera C.
      Renal function and attributable risk of death and cardiovascular hospitalization in participants with diabetes from a registry-based cohort.
      ].

      6.4.1 Metformin

      Patients with established CKD should use metformin cautiously, and it should be discontinued entirely if eGFR falls below 30 mL/min/1.73 m2 [
      • Duong J.K.
      • Roberts D.M.
      • Furlong T.J.
      • Kumar S.S.
      • Greenfield J.R.
      • Kirkpatrick C.M.
      • Day R.O.
      Metformin therapy in patients with chronic kidney disease.
      ].

      6.4.2 Sulphonylureas

      The use of SU in individuals with CKD is dependent on the level of renal impairment and risk of hypoglycaemia. Due to the high hypoglycaemia rates of glibenclamide, higher risk of hypoglycaemia in patients with renal disease, and the availability of safer sulphonylureas as well as other therapeutic options, glibenclamide should not be recommended in these patients.” [
      • Davies M.
      • Chatterjee S.
      • Khunti K.
      The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies.
      ]. In the ADVANCE study, intensive glucose lowering with gliclazide modified release (MR) significantly reduced the risk of new-onset microalbuminuria by 9%, macroalbuminuria by 30%, new or worsening nephropathy by 21% and end-stage renal disease by 65% [
      • Perkovic V.
      • Heerspink H.L.
      • Chalmers J.
      • Woodward M.
      • Jun M.
      • Li Q.
      • A.C. Group
      Intensive glucose control improves kidney outcomes in patients with type 2 diabetes.
      ]. A persistent benefit of this intensive glucose control with respect to ESRD was observed for 10 years after initiation of therapy [
      • Wong M.G.
      • Perkovic V.
      • Chalmers J.
      • Woodward M.
      • Li Q.
      • Cooper M.E.
      • Zoungas S.
      Long-term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON.
      ]. Gliclazide and gliclazide MR, with their lower risk of hypoglycaemia, does not require dose reduction in patients with eGFR >30 mL/min/1.73 m2 [
      • Ioannidis I.
      Diabetes treatment in patients with renal disease: is the landscape clear enough?.
      ]. Compared to other SUs, gliclazide treatment has been associated with lower risk of CVD and with weight neutrality [
      • Colagiuri S.
      • Matthews D.
      • Leiter L.A.
      • Chan S.P.
      • Sesti G.
      • Marre M.
      The place of gliclazide MR in the evolving type 2 diabetes landscape: a comparison with other sulfonylureas and newer oral antihyperglycemic agents.
      ].

      6.4.3 Glinides

      The insulin secretagogue glinides can also be used in patients with CKD as they are largely metabolised by the liver, though reduced dosages are suggested to limit the risk of hypoglycaemia [
      • Neumiller J.J.
      • Hirsch I.B.
      Management of hyperglycemia in diabetic kidney disease.
      ]. Repaglinide requires a greater number of tablets per day than other drugs, which hinders adherence to treatment in patients who are usually polymedicated, especially those with CKD.

      6.4.4 Dipeptidyl peptidase-4 inhibitors

      DPP-4is are an important option in patients with CKD who are not meeting their glycaemic targets. The different available DPP-4is are metabolised and eliminated in different ways and decreased doses in patients with varying levels of decreased kidney function may be required according to the prescribing instructions [
      • Davies M.
      • Chatterjee S.
      • Khunti K.
      The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies.
      ]. Of note, linagliptin is excreted almost entirely through a hepatic route and can be used at all stages of CKD without dose adjustment [
      • Davies M.
      • Chatterjee S.
      • Khunti K.
      The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies.
      ].

      6.4.5 Glucagon-like peptide-1 receptor agonists

      The GLP-1RA CVOTs have shown this drug family to have positive effects on renal function, particularly reducing albuminuria [
      • Sloan L.A.
      Review of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects.