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Background: In clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel. Methods: Adults with T2D treated with ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups. Results: Each propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0–54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82–1.11] (p = 0.566) and 0.71 [0.54–0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75–0.997] and 0.80 [0.64–0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m2/year [95%CI 0.11–0.73]; p = 0.008). Conclusion: Initiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function. [ABSTRACT FROM AUTHOR]

Background: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (− 1.9 to − 2.6%), body weight (− 6.6 to − 13.9%) and systolic blood pressure (SBP) (− 2.8 to − 12.6 mmHg) at the end of study treatment. Methods: Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials. Results: The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was − 1.3 to − 5.1 mmHg (tirzepatide 5 mg), − 1.7 to − 6.5 mmHg (tirzepatide 10 mg) and − 3.1 to − 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP. Conclusions: Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension. [ABSTRACT FROM AUTHOR]

Aim: To assess the potential gain in the number of life‐years free of a (recurrent) cardiovascular disease (CVD) event with optimal cardiovascular risk management (CVRM) and initiation of glucose‐lowering agents with proven cardiovascular benefit in people with type 2 diabetes (T2D). Materials and Methods: 9,416 individuals with T2D from the CAPTURE study, a non‐interventional, cross‐sectional, multinational study, were included. The diabetes lifetime‐perspective prediction model was used for calculating individual 10‐year and lifetime CVD risk. The distribution of preventive medication use was assessed according to predicted CVD risk and stratified for history of CVD. For the estimation of absolute individual benefit from lifelong preventive treatment, including optimal CVRM and the addition of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is), the model was combined with treatment effects from current evidence. Results: GLP‐1 RA or SGLT‐2i use did not greatly differ between patients with and without CVD history, while use of blood pressure‐lowering medication, statins and aspirin was more frequent in patients with CVD. Mean (standard deviation [SD]) lifetime benefit from optimal CVRM was 3.9 (3.0) and 1.3 (1.9) years in patients with and without established CVD, respectively. Further addition of a GLP‐1 RA and an SGLT‐2i in patients with CVD gave an added mean (SD) lifetime benefit of 1.2 (0.6) years. Conclusions: Life‐years gained free of (recurrent) CVD by optimal CVRM and the addition of a GLP‐1 RA or aSGLT‐2i is dependent on baseline CVD status. These results aid individualizing prevention and promote shared decision‐making in patients with T2D. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) are at increased risk for hospital admissions, and acute hospitalizations are associated with a worse prognosis. However, outcomes related to all‐cause hospital admissions (ACHAs) were often overlooked in trials that demonstrated the cardiovascular and kidney benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). This review includes a contemporary literature summary of emerging data regarding the effects of SGLT2 inhibitors and GLP‐1RAs on ACHAs. The role of SGLT2 inhibitors in preventing ACHAs was shown in exploratory investigations of several randomized controlled trials (RCTs) and was further supported by real‐world evidence (RWE). However, the association between GLP‐1RA use and lower ACHA risk was mainly shown through RWE, with minimal available RCT data. We also discuss the advantages and challenges of studying ACHAs. Finally, we propose an easily memorized ("ABCDE" acronym) clinical approach to evaluating T2D status and treatment in admitted patients, as they transition from hospital to community care. This systematic approach may assist clinicians in recognizing possible pitfalls in T2D management, thereby preventing subsequent hospitalizations and improving patient prognoses. While acute admission can sometimes be perceived as a management failure, it should also be viewed as an opportunity to take action to prevent the next hospitalization. [ABSTRACT FROM AUTHOR]

Aims: The LEADER trial demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1-RA) liraglutide reduces kidney and cardiovascular (CV) risk in patients with type 2 diabetes. We previously developed a Parameter Response Efficacy (PRE) score that translates multiple short-term risk marker changes, from baseline to first available follow-up measurement, into a predicted long-term drug effect on clinical outcomes. The objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of liraglutide in reducing the risk of kidney and CV outcomes. Methods: Short-term changes in glycated hemoglobin (HbA1c), systolic blood pressure (BP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, and potassium were monitored in the LEADER trial. Associations between risk markers and kidney or CV outcomes were established using a multivariable Cox proportional hazards model in a separate pooled database of 6,355 patients with type 2 diabetes. The regression coefficients were then applied to the short-term risk markers in the LEADER trial to predict the effects of liraglutide on kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) and CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and CV death) outcomes. Results: Liraglutide compared to placebo reduced HbA1c (1.4%), systolic BP (3.0 mmHg), UACR (13.2%), body weight (2.3 kg), hemoglobin (2.6 g/L), and increased HDL-cholesterol (0.01 mmol/L) (all p -values <0.01). Integrating multiple risk marker changes in the PRE score resulted in a predicted relative risk reduction (RRR) of 16.2% (95% CI 13.7–18.6) on kidney outcomes which was close to the observed RRR of 15.5% (95% CI -9.0–34.6). For the CV outcome, the PRE score predicted a 7.6% (95% CI 6.8–8.3) RRR, which was less than the observed 13.2% (95% CI 3.2–22.2) RRR. Conclusion: Integrating multiple short-term risk markers using the PRE score adequately predicted the effect of liraglutide on the composite kidney outcome. However, the PRE score underestimated the effect of liraglutide for the composite CV outcome, suggesting that the risk markers included in the PRE score do not fully capture the CV benefit of liraglutide. [ABSTRACT FROM AUTHOR]

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits. [ABSTRACT FROM AUTHOR]

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.Trial Registration: ClinicalTrials.gov Identifier: NCT03548987. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups. Methods: Data from patients in the PIONEER 3–5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients. Results: In total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: − 1.0 to − 1.5% and − 2.2 to − 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups. Conclusion: Oral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents. Trial Registration: Clinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8). [ABSTRACT FROM AUTHOR]

Aim: To assess the associations between baseline glucose‐lowering agents (GLAs) and cardiorenal outcomes with dapagliflozin versus placebo in the DECLARE‐TIMI 58 study. Materials and methods: DECLARE‐TIMI 58 assessed the cardiorenal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. This post hoc analysis elaborates the efficacy and safety outcomes by baseline GLA for treatment effect and GLA‐based treatment interaction. Results: At baseline, 14 068 patients (82.0%) used metformin, 7322 (42.7%) sulphonylureas, 2888 (16.8%) dipeptidyl peptidase‐4 inhibitors, 750 (4.4%) glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and 7013 (40.9%) insulin. Dapagliflozin reduced the composite of cardiovascular death (CVD) and hospitalization for heart failure (HHF) versus placebo regardless of baseline GLA, with greater benefit in the small group of patients with baseline use of GLP‐1 RAs (HR [95% CI] 0.37 [0.18, 0.78] vs. 0.86 [0.75, 0.98] in GLP‐1 RA users vs. non‐users, Pinteraction =.03). The overall HR for major adverse cardiovascular events (CVD, myocardial infarction or ischaemic stroke) was 0.93 (95% CI 0.84, 1.03) with dapagliflozin versus placebo, with no interaction by baseline GLA (Pinteraction >.05). The renal‐specific outcome was reduced with dapagliflozin versus placebo in the overall cohort (HR [95%CI] 0.53[0.43‐0.66]), with no interaction by baseline GLA (Pinteraction >.05). All of these outcomes were similar in those with versus those without baseline metformin use. Conclusions: The effects of dapagliflozin on cardiorenal outcomes were generally consistent regardless of baseline GLA, with consistent benefits regardless of baseline metformin use. The potential clinical benefit of combining sodium‐glucose co‐transporter‐2 inhibitors with GLP‐1 RAs, given some evidence of cardiovascular risk reduction with both classes, should be explored further. [ABSTRACT FROM AUTHOR]

Aim: To assess cardiorenal outcomes by baseline urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in the contemporary LEADER cohort. Materials and methods: LEADER was a multinational, double-blind trial. Patients with type 2 diabetes and high cardiovascular (CV) risk were randomized 1:1 to the glucagon-like peptide-1 analogue liraglutide (≤1.8 mg daily; n = 4668) or placebo (n = 4672) plus standard care and followed for 3.5 to 5 years. Primary composite outcomes were time to first non-fatal myocardial infarction, non-fatal stroke or CV death. Post hoc Cox regression analyses of outcomes by baseline UACR and eGFR subgroups were conducted with adjustment for baseline variables. Results: In the LEADER population, 1598 (17.5%), 2917 (31.9%), 1200 (13.1%), 1611 (17.6%), 845 (9.2%) and 966 (10.6%) had UACR = 0, >0 to <15, 15 to <30, 30 to <100, 100 to <300 and ≥300 mg/g, respectively. Increasing UACR and decreasing eGFR were linked with higher risks of the primary outcome, heart failure hospitalization, a composite renal outcome and death (P-values for the Cochran-Armitage test for trends were all <.0001). Across UACR and eGFR subgroups, risks of cardiorenal events and death were generally lower or similar with liraglutide versus placebo. Conclusions: In a contemporary type 2 diabetes population, increasing baseline UACR and declining eGFR were linked with higher risks of cardiorenal events and death. [ABSTRACT FROM AUTHOR]

Oral semaglutide is the first US Food and Drug Administration-approved oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes (T2D). Prior articles within this supplement reviewed the PIONEER trial program, which demonstrated that oral semaglutide reduced glycated hemoglobin and body weight when given to patients with uncontrolled T2D on various background therapies, and had a safety profile consistent with subcutaneous GLP-1RAs. This article provides guidance on integrating oral semaglutide into clinical practice in primary care. Patient populations with T2D who may gain benefit from oral semaglutide include those with inadequate glycemic control taking one or more oral glucose-lowering medication (e.g. after metformin), patients for whom weight loss would be beneficial, patients at risk of hypoglycemia, those who would historically have been considered for treatment with a subcutaneous GLP-1RA, and those receiving basal insulin who require treatment intensification. Like other GLP-1RAs, oral semaglutide is contraindicated in those with personal/family history of medullary thyroid carcinoma, and in those with multiple endocrine neoplasia syndrome type 2, as noted in a boxed warning in the prescribing information. Oral semaglutide has not been studied in those with a history of pancreatitis, is not recommended in patients with suspected/confirmed pancreatitis, and is not indicated in type 1 diabetes. When initiating oral semaglutide, gradual dose escalation is recommended to minimize the risk of gastrointestinal adverse events. As food and excess liquid reduce oral semaglutide absorption, patients should swallow the tablet with up to 4 fl oz/120 mL of water on an empty stomach upon waking, and should wait at least 30 minutes before eating, drinking, or taking other oral medications. Those managing patients should be aware of the potential impact of these dosing conditions on concomitant medications. When counseling patients, it is important to discuss these administration instructions, realistic therapeutic expectations, and strategies for mitigation of gastrointestinal events. Oral semaglutide provides a new option for add-on to initial T2D therapy (or later in the treatment paradigm), with the potential to enable more patients to benefit from the improvements in glycemic control, reductions in body weight, and low risk of hypoglycemia afforded by GLP-1RAs. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP- 1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a posthoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: -0.8%; 95% CI: -1.0, -0.6; p < 0.0001) and body weight (ETD: -2.5 kg; 95% CI: -3.2, -1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment. [ABSTRACT FROM AUTHOR]

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second‐line treatment after metformin and are often ranked at the same level as newer glucose‐lowering medications. Strong evidence now shows that sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT‐2is and GLP‐1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT‐2is and/or GLP‐1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second‐line agents continues to be acceptable in resource‐constrained settings. [ABSTRACT FROM AUTHOR]