Received: 30 November 2021 Revised: 22 February 2022 Accepted: 28 February 2022 DOI: 10.1111/dom.14684 REVIEW ARTICLE Sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes: Barriers and solutions for improving uptake in routine clinical practice Kamlesh Khunti MD, PhD1,2 | Serge Jabbour MD3 | Xavier Cos MD, PhD4,5 | Sunder Mudaliar MD6,7 | Christian Mende MD8 | Marc Bonaca MD9 | Paola Fioretto MD, PhD10 1 Diabetes Research Centre, College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, UK 2 NIHR Applied Research Collaboration - East Midlands, Leicester, UK 3 Thomas Jefferson University, Philadelphia, Pennsylvania, USA 4 Sant Marti de Provençals Primary Care Centres, Barcelona, Spain 5 Institut Català de la Salut. IDIAP Jordi Gol. DAP_Cat Study Group CIBERDEM, Universitat Autonoma de Barcelona, Barcelona, Spain 6 Department of Medicine, University of California, San Diego School of Medicine, San Diego, California, USA 7 Veterans Affairs Medical Center, San Diego, California, USA 8 Department of Medicine, University of California San Diego, La Jolla, California, USA 9 Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora CO; CPC Clinical Research, Aurora, Colorado, USA 10 Department of Medicine, University of Padua, Unite of Medical Clinic 3, Hospital of Padua, Padua, Italy Correspondence Kamlesh Khunti, FRCGP, FRCP, MD, PhD, Abstract FMedSci, Diabetes Research Centre, College Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of of Medicine, Biological Sciences and Psychology, University of Leicester, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal Gwendolen Road, Leicester LE5 4PW, UK. protection. However, uptake rates of these drugs remain low in patients with T2D, par- Email: kk22@leicester.ac.uk ticularly in subpopulations most likely to benefit from them. This review considers the Funding information potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines Funding was provided by AstraZeneca for the development of this manuscript and expert potential multidisciplinary recommendations to overcome these barriers. Safety con- participation in the roundtable discussion that cerns and a lack of clarity in and divergence of guidelines around the introduction of formed the basis of the content. SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians' perspective, including a general lack of understanding of the benefits associ- ated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiol- ogy, and nephrology) and country, with cardiologists the lowest prescribers, and endocri- nologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Diabetes Obes Metab. 2022;24:1187–1196. wileyonlinelibrary.com/journal/dom 1187 1188 KHUNTI ET AL. renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementa- tion of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D. KEYWORDS guidelines, sodium-glucose co-transporter-2 inhibitors, type 2 diabetes, uptake 1 | I N T RO DU CT I O N with placebo in patients with chronic kidney disease (CKD) with and without T2D in the DAPA-CKD trial (9.2% [197/2152] vs. Diabetes is a rising global healthcare burden associated with increased 14.5% [312/2152], respectively; P < .001). In the EMPA-REG mortality and reduced life expectancy because of associated cardio- OUTCOME trial, patients treated with empagliflozin had signifi- vascular, kidney, and liver disease, and it represents one of the top 10 cantly lower rates of death from cardiovascular causes (3.7% 1 leading causes of death globally. Approximately one in 11 adults vs. 5.9% in the placebo group; 38% relative risk reduction).13 worldwide now have diabetes, 90% of whom have type 2 diabetes Despite recent recommendations from the American Diabetes (T2D).2 Currently, most clinical practice guidelines and position state- Association (ADA), American College of Cardiology (ACC), Kidney Dis- ments recommend metformin as first-line therapy for individuals with ease: Improving Global Outcomes (KDIGO), and European Society of 3–5 T2D. Cardiology (ESC) in collaboration with European Association for the Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a com- Study of Diabetes (EASD) on the use of SGLT-2 inhibitors in T2D paratively new class of medications indicated for the treatment of management16–19 (Figure 1), prescription rates in patients with T2D T2D because they decrease kidney glucose reabsorption, thus increas- remain low in day-to-day clinical practice.20,21 The aim of this review 6,7 ing urinary glucose excretion and lowering blood glucose levels. In is to identify potential barriers to prescribing SGLT-2 inhibitors in turn, SGLT-2 inhibitors reduce intraglomerular pressure, thereby patients with T2D, addressing viewpoints from endocrinology, cardiol- preventing kidney disease and slowing its progression.8 The ren- ogy, nephrology, and primary care, and to propose targeted solutions oprotective effects associated with SGLT-2 inhibitors are generally to overcome these barriers. Opinions for this review were gathered observed over a wide range of estimated glomerular filtration rate during an expert roundtable discussion involving all authors. (eGFR) ranges and albuminuria categories.9 Results of large-scale randomised clinical trials of SGLT-2 inhibitors, such as dapagliflozin and empaglifozin, showed clear 2 | C O M P L E X I T Y A N D D I V E R G E N C E OF treatment benefits on cardiovascular and renal outcomes in G U I D E L I N E S M A Y R E P R E S E N T A BA R R I E R T O patients with T2D.10–14 In the CANVAS Program, patients with T H E I N I T I A T I O N OF SG LT - 2 I N H I BI T O R S BY T2D treated with canagliflozin had a lower risk of composite of CLINICI A NS death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke than those who received placebo (26.9 Several inconsistencies lie within the current clinical guidelines for vs. 31.5 participants per 1000 patient-years, respectively; hazard second-line therapy in T2D. The 2019 ADA/EASD consensus report ratio [HR] 0.86; 95% CI 0.75-0.97; P < .001 for non-inferior- recommends SGLT-2 inhibitors or glucagon-like peptide-1 receptor ity).10,11 Canagliflozin may also have a possible benefit with agonists (GLP-1 RAs) for: patients with CKD; those with established— 11 respect to the progression of albuminuria. In the DECLARE-TIMI or at high risk of developing—atherosclerotic cardiovascular disease; 58 trial, dapagliflozin reduced the risk of cardiovascular death or or heart failure.23 For individuals without these conditions, five non- hospitalization for heart failure by 17% (HR 0.83; 95% CI insulin second-line therapy options are listed, without a suggested 0.73-0.95; P = .005) and the cardiorenal secondary composite hierarchy of use.23 The American Association of Clinical Endocrinolo- 2 outcome (≥ 40% decrease in eGFR to < 60 ml/min/1.73m , new gists/American College of Endocrinology 2019 consensus statement end-stage renal disease, or death from renal or cardiovascular cau- suggests that SGLT-2 inhibitors and GLP-1 RAs may be preferred as ses) was significantly reduced with dapagliflozin versus placebo first-line therapy in patients with recent-onset T2D.23 Despite the (HR 0.76; 95% CI 0.67-0.87; P < .0001).12,14,15 In the DAPA-CKD shown cardioprotective benefits of GLP-1 RAs and SGLT-2 inhibitors, trial, the risk of a composite of a sustained decline in eGFR of at overall usage in UK clinical practice remains low in adults with T2D least 50%, end-stage kidney disease, or death from renal or car- and slightly lower in those with pre-existing CVD history, based on diovascular causes, was significantly lower with dapagliflozin than data from the Clinical Practice Research Datalink.25 Four oral KHUNTI ET AL. 1189 F I G U R E 1 An overview of recommendations by the ADA, ACC, KDIGO, and the ESC in collaboration with EASD on the use of SGLT-2 inhibitors in patient populations.16–18,86 ACC, American College of Cardiology; ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DKD, diabetic kidney disease; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; KDIGO, Kidney Disease: Improving Global Outcomes; SGLT-2 inhibitor, sodium-glucose co- transporter-2 inhibitor; T2D, type 2 diabetes treatment options (sulphonylureas, thiazolidinediones, SGLT-2 inhibi- Guidance on how to best address co-medications such as tors, or dipeptidyl peptidase-4 [DPP-4] inhibitors) are recommended diuretics, renin-angiotensin system inhibitors, and blood pressure by the American College of Physicians.26 medications could be more extensive. In addition, advice on how to Guidelines on when to initiate SGLT-2 inhibitors may benefit mitigate and manage DKA could be more prominent; research indi- from further clarity.17,27–30 The ADA guidelines suggest that SGLT-2 cates that very-low-carbohydrate or ketogenic diets should be inhibitors and GLP-1 RAs should be considered for patients with T2D avoided by patients receiving SGLT-2 inhibitors,35 however, many and CKD who require another agent in conjunction with metformin to guidelines do not currently reflect this information in detail. 31 target HbA1c levels or those who cannot tolerate or use metformin. Some clinicians may express uncertainty as to how to define spe- The lowering of HbA1c associated with SGLT-2 inhibitors has been cific indications such as congestive heart failure and heart failure with shown to be limited in patients with T2D with an eGFR of less than reduced ejection fraction (HFrEF), as their definitions may differ 45 ml/min/1.73m2.3 However, emerging evidence from clinical trials across clinical trials, or may be challenging to diagnose in general prac- suggests that SGLT-2 inhibitors have a cardioprotective and renal pro- tice.36,37 Furthermore, clinicians working in areas such as primary care tective role not associated with glucose lowering in patients with an may not necessarily be exposed to guidelines tailored to diverging eGFR as low as 25-30 ml/min/1.73m2.8,27,32 Indeed, the cardiorenal areas including nephrology, cardiology, and endocrinology. Therefore, benefits of SGLT-2 inhibitors are consistent across the eGFR range, consistency across specialty guidelines with regards to the use and 33 including stage 4 CKD. A reduction in heart failure hospitalization approved indications for SGLT-2 inhibitors would aid ease of imple- has also been observed across the different albuminuria subgroups in mentation. Suggestions on how to tailor current guidelines for multi- the CANVAS Program.34 disciplinary use are provided in Figure 2. 1190 KHUNTI ET AL. 3 | C L I N I C I A N S ' CO N C E R N S A N D Recommendations on the use of an SGLT-2 inhibitor to achieve PRESCRIBING TRENDS renoprotection for patients with T2D and diabetic kidney disease (DKD) based on eGFR threshold can also vary across SGLT-2 inhibi- Potential safety concerns associated with SGLT-2 inhibitors remain tors.42,44 Differences in the prescribing information across SGLT-2 an issue for some clinicians, particularly in primary care, which may inhibitors thus may cause confusion among clinicians and potentially underlie a reluctance to prescribe these medications (Figure 3), act as a barrier to their uptake. 38 despite the overall benefits in the mitigation of heart failure and An additional safety concern was highlighted in a Drug Safety CKD8 risks. For instance, acute, reversible eGFR decline may occur Communication issued by the US Food and Drug Administration in at around 4 weeks after SGLT-2 inhibitor initiation because of aug- 2015 warning of events adjudicated as DKA because of SGLT-2 inhib- mented distal nephron sodium delivery, ultimately leading to a itor use in T2D.45 The potential risk of DKA corresponded to a mar- 39 reduction in glomerular hyperfusion and hyperfiltration. This acute ked decline in overall SGLT-2 inhibitor use in the United States, eGFR decline led to concerns around the safety of SGLT-2 inhibitors despite events being rare in patients with T2D (~0.1%)44 when SGLT- because of the perceived risk of acute kidney injury (AKI) with these 2 inhibitors are correctly prescribed,35,45 even in severely ill, hospital- therapies, but recent data confirm that this eGFR decline is not ized patients.46 A key clinical strategy should be that clinicians and associated with AKI as these rare events mainly occur as a result of patients with T2D are informed of the risks of SGLT-2 inhibitors and volume depletion.39 Studies evaluating the eGFR slope suggest that provided with support prior to initiation in order to mitigate DKA risk. a larger eGFR dip generally shows a stronger benefit of SGLT-2 Data from the recently published DARE-19 trial suggest that SGLT-2 inhibitors compared with placebo; sustained benefit in decreasing inhibitors are well tolerated and associated with a low incidence of the eGFR slope has been shown for canagliflozin, dapagliflozin, confirmed DKA events in patients who had T2D at baseline (0.3% empagliflozin, and ertugliflozin compared with placebo.40,41 The car- [2/613] in the dapagliflozin group); these DKA events were non- diorenal benefits of SGLT-2 inhibitors were maintained regardless of severe and resolved after discontinuation.46 this eGFR decline. Therefore, this initial eGFR decline should not Other rare adverse events potentially related to empagliflozin, lead to safety concerns or be a barrier to the uptake of SGLT-2 canagliflozin, and ertugliflozin use include urosepsis (0.4% [17/4687] inhibitors.39 in the EMPA-REG trial)13 and pyelonephritis (0.3%; 13/4687).47–49 The permitted prescribing eGFR range for glycaemic control in The safety profile of SGLT-2 inhibitors is nevertheless well patients with T2D can vary across SGLT-2 inhibitors.42,43 established50 and many studies report benefits beyond glycaemic F I G U R E 2 A summary of potential ways in which guidelines for type 2 diabetes management could be improved for multidisciplinary use. eGFR, estimated glomerular filtration rate; SGLT-2, sodium-glucose co-transporter-2 KHUNTI ET AL. 1191 F I G U R E 3 Benefits of sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes and potential adverse events. BP, blood pressure; DKA, diabetic ketoacidosis; HbA1c, glycated haemoglobin; HF, heart failure. aHu M, et al.88; bPerkovic V, et al.11; cPereira MJ and Eriksson JW89; dLopaschuk GD and Verma S90; eMusso G, et al.91; fVardeny O and Vaduganathan M32; gWilliams SM and Ahmed SH92 F I G U R E 4 Potential interventions to overcome therapeutic inertia in patients with type 2 diabetes. CME, continuing medical education; HCPs, healthcare professionals. aZafar A, et al.54; bKhunti S, et al.53 control, including cardiovascular and kidney protection.11,38,51 Despite only 5.2% of patients with T2D who met the major eligibility criteria these benefits, therapeutic inertia among clinicians may play a role in for EMPA-REG OUTCOME in the United States were initiated on the lack of uptake of this class of drugs, with many clinicians continu- SGLT-2 inhibitors in clinical practice.57 However, prescription rates of ing to focus on glycaemic control as the primary outcome in the treat- SGLT-2 inhibitors in the United States appear to have increased from ment of T2D.21,52 There may be potential interventions to overcome 2013 to 2020 in patients with DKD, particularly those aged younger 53,54 therapeutic inertia (Figure 4). The ADA have also recognized the than 65 years.58 potential impact of therapeutic inertia and have proposed a robust ini- SGLT-2 inhibitor prescribing trends appear to vary between spe- tiative to combat this, such as leveraging electronic health record and cialties and countries.59 A 2021 study of 440 599 patients with T2D clinical-support tools, developing a registry of effective strategies, and identified large global variations in SGLT-2 inhibitor prescribing trends 55 targeting payer policies. across 13 countries, with Canada and Israel showing the steepest A UK study of 81 532 patients with T2D conducted in 2017 indi- increases. With regard to trends between specialties, data suggest cated that DPP-4 and SGLT-2 inhibitors represented the most com- that endocrinologists are the most probable to initiate an SGLT-2 mon second- and fourth-line therapies in primary care, respectively. inhibitor (10%-15% higher initiation than for non-endocrine special- An observed rapid increase in the use of these two drugs from 2010 ties; P < .001).45 However, less than 10% and 20% of UK-60 and to 2017 correlated with overall improvements in weight gain and United States-based61 patients with diabetes, respectively, see an rates of hypoglycaemia, although a causal relationship cannot be endocrinologist. Cardiologists are among the lowest prescribers of inferred from these results.56 Another study found that 19.1%-27.6% SGLT-2 inhibitors (< 1%-< 5%),57,58,62 possibly because of their con- of 238 619 patients with diabetes in Australia, Canada, England, and cerns regarding adverse effects such as lower limb amputations or Scotland were prescribed DPP-4 inhibitors, while only 10.1%-15.3% drug interactions.32 However, the recent additions to the ESC guide- 4 were prescribed SGLT-2 inhibitors. A further study observed that lines, which recommend dapagliflozin or empagliflozin for patients 1192 KHUNTI ET AL. with HFrEF regardless of diabetes status, may encourage the uptake being more likely to request a prescription drug in response to DTC of SGLT-2 inhibitors among cardiologists.63 In addition, primary care advertising than other ethnic groups.74 A large cohort study identified physicians may not be fully aware of the cardiovascular and renal pro- an independent association of Black race (adjusted odds ratio [aOR] tective roles of SGLT-2 inhibitors in T2D because of fewer educa- 0.83; 95% CI 0.81-0.85; P < .001) and Asian race (aOR 0.94; 95% CI tional opportunities regarding cardiovascular and renal disease in 0.90-0.98; P < .001) with lower rates of SGLT-2 inhibitor use com- relation to diabetes, potentially leading to therapeutic inertia.64 Lack pared with Caucasians.73 Female patients (aOR 0.84; 95% CI of communication between clinicians may act as a further barrier to 0.82-0.85; P < .001) were also less probable to receive an SGLT-2 prescribing SGLT-2 inhibitors, especially if clearance is believed to be inhibitor than male patients.73 Paradoxically, young, low-risk, non- required from the patient's general practitioner (GP) or endocrinolo- Black patients with commercial health insurance have been found to gist.65 Therefore, collaborative care models with joint visits with clini- be the most probable to be treated with SGLT-2 inhibitors,45 while cians from different specialties including endocrinology, nephrology, patients with heart failure, kidney disease, prior hypoglycaemia, and primary care, and cardiology may streamline communication and opti- myocardial infarction are less probable to be prescribed an SGLT-2 mize therapeutic outcomes. inhibitor, despite evidence supporting the benefits of their use in these patients.45 Prescription rate disparities have also been reported in the UK, where Black and Asian patients with T2D may be less likely 4 | P A T I E NT CH A R A C T E R I S T I C S M A Y to be prescribed GLP-1 RAs and SGLT-2 inhibitors than other ethnic I N F L U E N C E SG L T - 2 I N H I B I T O R U P T A K E groups.75 Concern regarding adverse effects including genital mycotic infec- tions and polyuria may serve to inhibit some patients' willingness to 5 | COST-EFFECTIVENESS OF SGLT-2 commence taking SGLT-2 inhibitors.45 Conversely, weight loss and I N HI B I T O R S R E M A I N S A N OB S T A C LE HbA1c-lowering benefits appear to motivate patients to initiate SGLT-2 inhibitors, which may be attributed to the majority of Affordability and access to SGLT-2 inhibitors represent significant patients with T2D being overweight or obese.66 Reluctance to initi- barriers to their uptake in patients with T2D (including those with ate SGLT-2 inhibitors may be curbed if the various benefits and side heart failure, CKD, and albuminuria), particularly in the United States, effects are thoroughly explained in a balanced manner, and if patients because of the heterogeneity in costs within the healthcare sys- feel included in the decision-making process. The ADA and EASD tem.32,76 A 2021 study provided data of US median monthly average guidelines provide an effective integration of patient-centred strate- wholesale prices (AWP) of SGLT-2 inhibitors; median monthly AWP gies to achieve optimal outcomes in those with T2D, but may lack in were comparable across SGLT-2 inhibitors, costing US$621, US$627, parallel guidance and more targeted education on antidiabetic drug and US$622 for dapagliflozin, empagliflozin, and canagliflozin, respec- options that could be fully understood on a patient level, therefore tively, although out-of-pocket co-pay costs are often considerably clinician–patient communication is paramount.67 Patients with a lower.27 Other non-insulin glucose-lowering agents were much more more thorough understanding of antidiabetic medications have been affordable, with the reported monthly AWP for sulphonylureas rang- reported to show better glycaemic control and this could improve ing from US$52 to US$93.27 However, SGLT-2 inhibitors may be 68 adherence. Diabetes self-management education is also encour- more cost-effective than insulin and sulphonylureas77 and are associ- aged to facilitate the skills and knowledge necessary for diabetes ated with increased quality-adjusted life years because of weight loss self-care, including understanding the prevalence of cardiovascular and decreased prevalence of cardiovascular morbidities;78 payers and (> 30%)69 and renal (> 20%)70 complications of diabetes and how formulary committees should be made aware of these key data.79 The they can be prevented or delayed with the use of SGLT-2 2019 ADA/EASD consensus report further highlights that choosing inhibitors.71 an antidiabetic drug class with the lowest acquisition cost can be an In the United States, patients may be influenced by direct-to-con- issue when managing patients with T2D whose HbA1c levels are sumer (DTC) advertising of drugs, with those marketed to induce above target.23 weight loss selected preferentially by patients beyond medications Variations in US health insurance coverage are also a key factor in that possess less visible benefits such as functional heart or kidney prescription rates in T2D, with some insurance companies covering improvement. Such preferences could be—in part—attributed to a lack only selected SGLT-2 inhibitors: for instance, ertugliflozin is offered of information on the role of SGLT-2 inhibitors in preventing progres- by only 6% of coverage plans.80 Cost and insurance coverage will 72 sion to heart and renal failure. therefore largely determine which SGLT-2 inhibitor is selected.81 In Race/ethnicity, gender, age, and socioeconomic differences are the United States, patient insurance co-payment monthly costs can evident in SGLT-2 inhibitor uptake rates because of poorer access to range from under US$10 to US$600 for SGLT-2 inhibitors;82 patients quality healthcare and possible biases in healthcare delivery. In the from high-income households (aOR 1.08; 95% CI 1.05-1.10; P < .001) United States, Black adults are among those least likely to receive an are thus more probable to receive SGLT-2 inhibitors for patients with SGLT-2 inhibitor, despite this patient subset experiencing a dispropor- a median annual income of at least US$100 000.73 The co-payment 73 tionately higher burden of cardiovascular and kidney diseases and system is therefore highly individual, and medication use is dictated KHUNTI ET AL. 1193 by what each patient is able to afford on a case-by-case basis, espe- barriers to SGLT-2 inhibitor uptake in current clinical practice and pro- cially in those on multiple T2D, hypertension, and cholesterol posed solutions are provided in Figure 5. medications. In Europe, prescription rates are less affected by health insurance coverage, however, other factors appear to affect uptake. Reimburse- 6. C ONCL US I ONS ment criteria may vary across countries, with diabetes-related perfor- mance indicators such as HbA1c levels being incorporated into payer The decision to initiate SGLT-2 inhibitor therapy in T2D is probably performance measures.79 For example, in Italy, reimbursement legisla- impacted by multiple factors including inconsistencies in guideline rec- tion prevents GPs from prescribing SGLT-2 inhibitors without special- ommendations, safety concerns, patient characteristics, cost consider- ist approval, representing a large barrier to SGLT-2 initiation. As a ations, and the specialty of the healthcare provider. In order to result, the most common initial treatment for T2D is metformin in improve uptake, further education of both patients and providers both monotherapy and combination therapy with sulphonylureas.83 regarding the benefits versus the risks of SGLT-2 inhibitors in patients Primary care practitioners are able to prescribe SGLT-2 inhibitors in with T2D is needed. Support, particularly early in the treatment Spain with no major reimbursement limitations.84 However, primary course, and with standpoints from all relevant specialties, including care practitioners are alerted when exceeding the estimated prescrip- cardiology, nephrology, endocrinology, and primary care, independent tion rate threshold. This acts as an indicator rather than as a strict bar- of glycaemic benefits, is needed. rier, but may discourage some clinicians from prescribing SGLT-2 With regard to guidelines, safety issues associated with SGLT-2 inhibitors. No such SGLT-2 inhibitor prescription restrictions exist in inhibitors must be clarified, with clear guidance on patient eligibility the UK, yet 2017 data highlighted low prescribing trends nonetheless, provided, and indications such as CKD, heart failure, and cardiovascu- with DPP-4 inhibitors initiated most frequently (57%), followed by lar disease must be defined clearly to provide further clarity for SGLT-2 inhibitors (18%).85 These data are consistent with the NICE prescribing clinicians. Formulary committees should consider the cost- guidelines, which recommend DPP-4 and SGLT-2 inhibitors for first effectiveness of SGLT-2 inhibitor medications and quality-adjusted 86 and second optimization of treatment, respectively. The multiple life years. Ultimately, more uniform implementation of this therapy in FIGURE 5 A summary of barriers to the uptake of sodium-glucose co-transporter-2 (SGLT-2) inhibitors in clinical practice and proposed solutions 1194 KHUNTI ET AL. line with trial findings and labelled indications could improve out- 2. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes comes for patients with T2D. prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. ACKNOWLEDGEMEN TS 3. American Diabetes Association professional practice committee. Medical writing support was provided by Sally Sheldon and Jonathon 9. Pharmacologic approaches to glycemic treatment: standards of Ackroyd, Springer Healthcare Ltd, and was funded by AstraZeneca. medical Care in Diabetes—2022. Diabetes Care. 2021;45- (Supplement_1):S125-S143. 4. Greiver M, Havard A, Bowles JK, et al. Trends in diabetes medication use CONF LICT OF IN TE RE ST in Australia, Canada, England, and Scotland: a repeated cross-sectional KK has acted as a consultant, speaker or received grants for analysis in primary care. Br J Gen Pract. 2021;71(704):e209-e218. investigator-initiated studies for AstraZeneca, Novartis, Novo Nordisk, 5. Seidu S, Cos X, Brunton S, et al. A disease state approach to the phar- macological management of type 2 diabetes in primary care: a posi- Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer tion statement by primary care diabetes Europe. Prim Care Diabetes. Ingelheim, Bayer, Berlin-Chemie AG/Menarini Group, Janssen, and 2021;15(1):31-51. Napp. He is supported by the National Institute for Health Research 6. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target (NIHR) Applied Research Collaboration East Midlands (ARC EM) and for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12(2):78-89. the NIHR Leicester Biomedical Research Centre (BRC). CM received 7. Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treat- honoraria for speaking engagements and/or advisory board meetings ment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(10):556-577. for Boehringer Ingelheim, Lilly, Janssen, AstraZeneca, and Bayer. XC 8. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in served as an advisor or consultant for: AstraZeneca, Boehringer patients with chronic kidney disease. N Engl J Med. 2020;383(15): Ingelheim, Esteve, Lilly, Novartis, Novo Nordisk, Sanofi Diabetes, and 1436-1446. 9. Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 Sanofi Pasteur; served as a speaker or a member of a speakers' bureau inhibitors in type 2 diabetes over a spectrum of cardiovascular and for: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, renal risk. Cardiovascular Diabetol. 2020;19(1):196. Sanofi Diabetes, and Sanofi Pasteur; received grants for clinical 10. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovas- research from: AstraZeneca, Boehringer Ingelheim, Novartis, and cular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7): 644-657. Sanofi. SJ works as a consultant for AstraZeneca and Eli Lilly. SM 11. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal out- served as a member of a speakers' bureau for AstraZeneca. PF comes in type 2 diabetes and nephropathy. N Engl J Med. 2019; received speaker and advisory member fees from Astra Zeneca, 380(24):2295-2306. Boehringer Ingelheim, Lilly, Mundipharma, and Bayer. MB had grant 12. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. support provided to CPC Clinical Research by Agios Pharmaceuticals, 13. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular Amgen, ARCA BioPharma, AstraZeneca, Bayer, Better Therapeutics, outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; BMS, Cardiol Therapeutics, CellResearch, Heart Flow, HDL Therapeu- 373(22):2117-2128. tics, Jansen, Merck, NovoNordisk, Regio, Virta, and Wraser, and to 14. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. BWH from AstraZeneca for DECLARE-TIMI 58. 2019;139(22):2528-2536. 15. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on AUTHOR CONTRIBUTIONS development and progression of kidney disease in patients with type All authors contributed to the roundtable discussion, the drafting of 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606-617. the manuscript, and critical revision for intellectual content. 16. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus deci- sion pathway on novel therapies for cardiovascular risk reduction in P EE R R EV I E W patients with type 2 diabetes: a report of the American College of The peer review history for this article is available at https://publons. Cardiology Solution set Oversight Committee. J Am Coll Cardiol. com/publon/10.1111/dom.14684. 2020;76(9):1117-1145. 17. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on dia- betes, pre-diabetes, and cardiovascular diseases developed in collabo- DATA AVAI LAB ILITY S TATEMENT ration with the EASD: the task force for diabetes, pre-diabetes, and Data sharing is not applicable to this article as no new data were cre- cardiovascular diseases of the European Society of Cardiology (ESC) ated or analyzed in this study. and the European Association for the Study of diabetes (EASD). Eur Heart J. 2019;41(2):255-323. ORCID 18. Chaplin S. Primary care prescribing for diabetes: latest figures Kamlesh Khunti https://orcid.org/0000-0003-2343-7099 show upward trend in volume and cost. Pract Diabetes. 2019;36(1): Serge Jabbour https://orcid.org/0000-0002-4080-0470 30-32. 19. de Boer IH, Caramori ML, Chan JCN, et al. Executive summary of the Paola Fioretto https://orcid.org/0000-0003-3445-0387 2020 KDIGO diabetes management in CKD guideline: evidence- based advances in monitoring and treatment. Kidney Int. 2020;98(4): RE FE R ENC E S 839-848. 1. Lin X, Xu Y, Pan X, et al. Global, regional, and national burden and 20. American Diabetes Association. 10. Cardiovascular disease and risk trend of diabetes in 195 countries and territories: an analysis from management: standards of medical Care in Diabetes—2022. Diabetes 1990 to 2025. Sci Rep. 2020;10(1):14790. Care. 2021;45(Supplement_1):S144-S174. KHUNTI ET AL. 1195 21. Mata-Cases M, Franch-Nadal J, Real J, Vlacho B, Go  mez-García A, 40. Kraus BJ, Weir MR, Bakris GL, et al. Characterization and implications Mauricio D. Evaluation of clinical and antidiabetic treatment charac- of the initial estimated glomerular filtration rate ‘dip’ upon sodium- teristics of different sub-groups of patients with type 2 diabetes: data glucose cotransporter-2 inhibition with empagliflozin in the EMPA- from a Mediterranean population database. Prim Care Diabetes. 2021; REG OUTCOME trial. Kidney Int. 2021;99(3):750-762. 15(3):588-595. 41. Gregg LP, Navaneethan SD. Are all SGLT2 inhibitors created equal? 22. Kanumilli N, Brunton S, Cos X, et al. Global survey investigating cau- Clin J Am Soc Nephrol. 2021;16(9):1309-1311. ses of treatment inertia in type 2 diabetes cardiorenal risk manage- 42. Jeong SJ, Lee SE, Shin DH, Park IB, Lee HS, Kim K-A. Barriers to initi- ment. J Diabetes Complications. 2021;35(3):107813. ating SGLT2 inhibitors in diabetic kidney disease: a real-world study. 23. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management BMC Nephrol. 2021;22(1):177. of hyperglycemia in type 2 diabetes, 2018. A consensus report by 43. NICE. SGLT-2 Inhibitors. 2021. https://cks.nice.org.uk/topics/ the American Diabetes Association (ADA) and the European Asso- diabetes-type-2/prescribing-information/sglt-2-inhibitors/. Accessed ciation for the Study of diabetes (EASD). Diabetes Care. 2020; February 2022. 43(2):487-493. 44. U.S. Food and Drug Administration. FDA Revises Labels of SGLT2 24. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by Inhibitors for Diabetes to Include Warnings about Too Much Acid in the American Association of Clinical Endocrinologists and American the Blood and Serious Urinary Tract Infections. 2020. https://www. College of endocrinology on the comprehensive type 2 diabetes man- fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2- agement algorithm. Endocr Pract. 2019;25(1):69-101. inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and- 25. Farmer RE, Beard I, Raza SI, et al. Prescribing in type 2 diabetes serious. Accessed February 2022. patients with and without cardiovascular disease history: a descrip- 45. The Renal Association. Clinical Practice Guidelines for Management of tive analysis in the UKCPRD. Clin Ther. 2021;43(2):320-335. Hyperglycaemia in Adults with Diabetic Kidney Disease. UK Kidney Asso- 26. Shin JI. Second-line glucose-lowering therapy in type 2 diabetes ciation; 2021. https://ukkidney.org/sites/renal.org/files/Managing% mellitus. Curr Diab Rep. 2019;19(8):54. 20hyperglycaemia%20in%20people%20with%20DKD_final%20draft. 27. American Diabetes Association. 9. Pharmacologic approaches to pdf. Accessed February 2022. glycemic treatment: standards of medical Care in Diabetes-2021. Dia- 46. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and betes Care. 2021;44(Suppl 1):S111-s124. related events in the canagliflozin type 2 diabetes clinical program. 28. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by Diabetes Care. 2015;38(9):1680-1686. the American Association of Clinical Endocrinologists and American Col- 47. McCoy RG, Dykhoff HJ, Sangaralingham L, et al. Adoption of new lege of endocrinology on the comprehensive type 2 diabetes managament glucose-lowering medications in the U.S.-the case of SGLT2 inhibi- algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107-139. tors: nationwide cohort study. Diabetes Technol Ther. 2019;21(12): 29. de Boer IH, Caramori ML, Chan JC, et al. Executive summary of the 702-712. 2020 KDIGO diabetes management in CKD guideline: evidence- 48. Kosiborod MN, Esterline R, Furtado RHM, et al. Dapagliflozin in based advances in monitoring and treatment. Kidney Int. 2020; patients with cardiometabolic risk factors hospitalised with COVID-19 2098(2024):2839-2848. (DARE-19): a randomised, double-blind, placebo-controlled, phase 30. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in 3 trial. Lancet Diab Endocrinol. 2021;2029(2029):2586-2594. the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021; 49. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on 46:101102. fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol. 31. American Diabetes Association. Addendum. 11. Microvascular com- 2016;101(1):157-166. plications and foot care: standards of medical Care in Diabetes— 50. Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on 2021: Diabetes Care 2021; 44 (Suppl. 1): S151–S167. Diabetes Care. amputation risk in type 2 diabetes: the CANVAS program. 2021;44(9):2186-2187. Diabetologia. 2019;62(6):926-938. 32. Vardeny O, Vaduganathan M. Practical guide to prescribing sodium- 51. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes glucose cotransporter 2 inhibitors for cardiologists. JACC Heart Fail. with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15): 2019;7(2):169-172. 1425-1435. 33. Chertow GM, Vart P, Jongs N, et al. Effects of dapagliflozin in stage 52. Scheen AJ. Efficacy and safety profile of SGLT2 inhibitors in patients 4 chronic kidney disease. J Am Soc Nephrol. 2021;32(9):2352-2361. with type 2 diabetes and chronic kidney disease. Expert Opin Drug 34. Fontes-Carvalho R, Santos-Ferreira D, Raz I, Marx N, Ruschitzka F, Saf. 2020;19(3):243-256. Cosentino F. Protective effects of SGLT-2 inhibitors across the car- 53. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: diorenal continuum: two faces of the same coin. Eur J Prev Cardiol. weighing the risks and benefits. Diabetologia. 2018;61(10):2118- 2021;zwab034. 2125. 35. Monami M, Nreu B, Zannoni S, Lualdi C, Mannucci E. Effects of 54. Schernthaner G, Shehadeh N, Ametov AS, et al. Worldwide inertia to SGLT-2 inhibitors on diabetic ketoacidosis: a meta-analysis of ran- the use of cardiorenal protective glucose-lowering drugs (SGLT2i and domised controlled trials. Diabetes Res Clin Pract. 2017;130:53-60. GLP-1 RA) in high-risk patients with type 2 diabetes. Cardiovasc 36. Bashier A, Bin Hussain A, Abdelgadir E, Alawadi F, Sabbour H, Diabetol. 2020;19(1):185. Chilton R. Consensus recommendations for management of patients 55. Khunti S, Khunti K, Seidu S. Therapeutic inertia in type 2 diabetes: with type 2 diabetes mellitus and cardiovascular diseases. Diabetol prevalence, causes, consequences and methods to overcome inertia. Metab Syndr. 2019;11:80. Ther Adv Endocrinol Metab. 2019;10:2042018819844694. 37. Smeets M, De Witte P, Peters S, Aertgeerts B, Janssens S, Vaes B. 56. Zafar A, Davies M, Azhar A, Khunti K. Clinical inertia in management Think-aloud study about the diagnosis of chronic heart failure in of T2DM. Prim Care Diabetes. 2010;4(4):203-207. Belgian general practice. BMJ Open. 2019;9(3):e025922. 57. Gabbay RA, Kendall D, Beebe C, et al. Addressing therapeutic inertia 38. McMurray JJ, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients in 2020 and beyond: a 3-year initiative of the American Diabetes with heart failure and reduced ejection fraction. N Engl J Med. 2019; Association. Clin Diabetes. 2020;38(4):371-381. 381(21):1995-2008. 58. Dennis JM, Henley WE, McGovern AP, et al. Time trends in prescrib- 39. Heerspink HJL, Cherney DZI. Clinical implications of an acute dip in ing of type 2 diabetes drugs, glycaemic response and risk factors: a eGFR after SGLT2 inhibitor initiation. Clin J Am Soc Nephrol. 2021; retrospective analysis of primary care data, 2010-2017. Diabetes Obes 16(8):1278-1280. Metab. 2019;21(7):1576-1584. 1196 KHUNTI ET AL. 59. Arnold SV, Inzucchi SE, Tang F, et al. Real-world use and modeled 78. McCoy IE, Han J, Montez-Rath ME, Chertow GM, Rhee JJ. Patient and impact of glucose-lowering therapies evaluated in recent cardiovascu- provider characteristics associated with sodium-glucose cotransporter lar outcomes trials: an NCDR® research to practice project. Eur J Prev 2 inhibitor prescription in patients with diabetes and Proteinuric Cardiol. 2017;24(15):1637-1645. chronic kidney disease. Clin Diabetes. 2020;38(3):240-247. 60. Harris ST, Patorno E, Zhuo M, Kim SC, Paik JM. Prescribing trends of 79. Hong D, Si L, Jiang M, et al. Cost effectiveness of sodium-glucose Antidiabetes medications in patients with type 2 diabetes and dia- cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) betic kidney disease, a cohort study. Diabetes Care. 2021;44(10): receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors: a 2293-2301. systematic review. Pharmacoeconomics. 2019;37(6):777-818. 61. Khunti K, Kosiborod M, Kim DJ, et al. Cardiovascular outcomes with 80. McEwan P, Bennett H, Khunti K, et al. Assessing the cost-effectiveness sodium–glucose cotransporter-2 inhibitors vs other glucose-lowering of sodium–glucose cotransporter-2 inhibitors in type 2 diabetes mellitus: drugs in 13 countries across three continents: analysis of CVD-REAL a comprehensive economic evaluation using clinical trial and real-world data. Cardiovasc Diabetol. 2021;20(1):159. evidence. Diabetes Obes Metab. 2020;22(12):2364-2374. 62. Andrade LF, Rapp T, Sevilla-Dedieu C. Exploring the determinants of 81. Lopez JM, Macomson B, Ektare V, Patel D, Botteman M. Evaluating endocrinologist visits by patients with diabetes. Eur J Health Econ. drug cost per response with SGLT2 inhibitors in patients with type 2016;17(9):1173-1184. 2 diabetes mellitus. Am Health Drug Benef. 2015;8(6):309-318. 63. Saudek CD. The role of primary care professionals in managing diabe- 82. Luo J, Feldman R, Rothenberger SD, Hernandez I, Gellad WF. tes. Clin Diabetes. 2002;20(2):65-66. Coverage, formulary restrictions, and out-of-pocket costs for sodium- 64. Dave CV, Schneeweiss S, Wexler DJ, Brill G, Patorno E. Trends in glucose cotransporter 2 inhibitors and glucagon-like peptide 1 recep- clinical characteristics and prescribing preferences for SGLT2 inhibi- tor agonists in the Medicare part D program. JAMA Netw Open. 2020; tors and GLP-1 receptor agonists, 2013-2018. Diabetes Care. 2020; 3(10):e2020969. 43(4):921-924. 83. Simes BC, MacGregor GG. Sodium-glucose cotransporter-2 (SGLT2) 65. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for inhibitors: a clinician's guide. Diabetes Metab Syndr Obes. 2019;12: the diagnosis and treatment of acute and chronic heart failure: devel- 2125-2136. oped by the task force for the diagnosis and treatment of acute and 84. Genuardi MV, Mather PJ. The dawn of the four-drug era? SGLT2 inhi- chronic heart failure of the European Society of Cardiology (ESC) with bition in heart failure with reduced ejection fraction. Ther Adv Cardi- the special contribution of the Heart Failure Association (HFA) of the ovasc Dis. 2021;15:17539447211002678. ESC. Eur Heart J. 2021;42(36):3599-3726. 85. Moreno Juste A, Menditto E, Orlando V, et al. Treatment patterns of dia- 66. Lavoie KL, Rash JA, Campbell TS. Changing provider behavior in the betes in Italy: a population-based study. Front Pharmacol. 2019;10:870. context of chronic disease management: focus on clinical inertia. Ann 86. Fadini GP, Tentolouris N, Caballero Mateos I, Bellido Castañeda V, Rev Pharmacol Toxicol. 2017;57:263-283. Morales PC. A multinational real-world study on the clinical charac- 67. Rushforth B, McCrorie C, Glidewell L, Midgley E, Foy R. Barriers to teristics of patients with type 2 diabetes initiating dapagliflozin in effective management of type 2 diabetes in primary care: qualitative southern Europe. Diabetes Ther. 2020;11(2):423-436. systematic review. Br J Gen Prac. 2016;66(643):e114-e127. 87. Excellence NIfHaC. Managing blood glucose in adults with type 2 diabe- 68. Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes tes. https://pathways.nice.org.uk/pathways/type-2-diabetes-in-adults/ mellitus and obesity. Diabetes Metab Syndr Obes. 2014;7:587. managing-blood-glucose-in-adults-with-type-2-diabetes. Accessed May 69. Ha JF, Longnecker N. Doctor-patient communication: a review. 28, 2021. Ochsner J. 2010;10(1):38-43. 88. Hu M, Cai X, Yang W, Zhang S, Nie L, Ji L. Effect of hemoglobin A1c 70. McPherson ML, Smith SW, Powers A, Zuckerman IH. Association reduction or weight reduction on blood pressure in glucagon-like between diabetes patients' knowledge about medications and their peptide-1 receptor agonist and sodium-glucose cotransporter-2 blood glucose control. Res Social Adm Pharm. 2008;4(1):37-45. inhibitor treatment in type 2 diabetes mellitus: a meta-analysis. J Am 71. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascu- Heart Assoc. 2020;9(7):e015323. lar disease in type 2 diabetes: a systematic literature review of scien- 89. Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the tific evidence from across the world in 2007–2017. Cardiovasc treatment of obesity. Drugs. 2019;79(3):219-230. Diabetol. 2018;17(1):1-19. 90. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of 72. Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art kidney disease: world wide difference of prevalence and risk factors. review. J Am Coll Cardiol Basic Trans Sci. 2020;5(6):632-644. J Nephropharmacol. 2016;5(1):49. 91. Musso G, Saba F, Cassader M, Gambino R. Diabetic ketoacidosis with 73. de Boer IH, Caramori ML, Chan JC, et al. KDIGO 2020 clinical prac- SGLT2 inhibitors. BMJ. 2020;371:m4147. tice guideline for diabetes management in chronic kidney disease. 92. Williams SM, Ahmed SH. 1224-P: Improving compliance with SGLT2 Kidney Int. 2020;98(4):S1-S115. inhibitors by reducing the risk of genital mycotic infections: the outcomes 74. Klara K, Kim J, Ross JS. Direct-to-consumer broadcast advertisements of personal hygiene advice. Diabetes. 2019;68(Supplement_1):1224. for pharmaceuticals: off-label promotion and adherence to FDA guidelines. J Gen Intern Med. 2018;33(5):651-658. 75. Eberly LA, Yang L, Eneanya ND, et al. Association of race/ethnicity, gender, and socioeconomic status with sodium-glucose cotransporter 2 inhibitor use among patients with diabetes in the US. JAMA Netw How to cite this article: Khunti K, Jabbour S, Cos X, et al. Open. 2021;4(4):e216139. Sodium-glucose co-transporter-2 inhibitors in patients with 76. Datti B, Carter MW. The effect of direct-to-consumer advertising on type 2 diabetes: Barriers and solutions for improving uptake in prescription drug use by older adults. Drugs Aging. 2006;23(1):71-81. routine clinical practice. Diabetes Obes Metab. 2022;24(7): 77. Whyte MB, Hinton W, McGovern A, et al. Disparities in glycaemic control, monitoring, and treatment of type 2 diabetes in England: a 1187-1196. doi:10.1111/dom.14684 retrospective cohort analysis. PLoS Med. 2019;16(10):e1002942.