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HYPERINSULINAEMIA ISSN 1811-6515 THE SOUTH AFRICAN JOURNAL OF Diabetes & Vascular Disease Corresponding Editor DR FA MAHOMED Head of Internal Medicine Madadeni Hospital Newcastle KwaZulu-Natal Consulting Editor PROF J-C MBANYA National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa PROF R DELPORT Department of Family Medicine, University of Pretoria DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg PROF WF MOLLENTZE Head of Department of Internal Medicine, University of the Free State, Bloemfontein PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK VOLUME 20 NUMBER 2 • NOVEMBER 2023 www.diabetesjournal.co.za CONTENTS 23 From the Editor’s Desk FA Mahomed Research Article 24 Comparison of early postoperative results in patients with and without diabetes with low ejection fraction and normal serum creatinine values who underwent coronary artery bypass operation C Yücel, İ Özgöl Review 29 The cardiovascular benefits of new diabetes drugs A Maney, K Hanmonth Diabetes News 34 The importance of exercise in people living with diabetes Women and diabetes: Pregnancy is an opportunity for intervention The link between diabetes and arrhythmias Turmeric could benefit diabetes patients: Thai review
Production Editor SHAUNA GERMISHUIZEN TEL: 021 785 7178 FAX: 086 628 1197 e-mail: shauna@clinicscardive.com Financial & Production Co-ordinator ELSABÉ BURMEISTER TEL: 021 976 8129 CELL: 082 775 6808 FAX: 086 664 4202 e-mail: elsabe@clinicscardive.com Content Manager MICHAEL MEADON (Design Connection) TEL: 021 976 8129 FAX: 086 655 7149 e-mail: michael@clinicscardive.com The South African Journal of Diabetes and Vascular Disease is published twice a year for Clinics Cardive Publishing (Pty) Ltd and printed by Durbanville Commercial Printers/Tandym Print. Online Services: Design Connection. All correspondence to be directed to: THE EDITOR PO BOX 1013 DURBANVILLE 7551 or elsabe@clinicscardive.com TEL: 021 976 8129 FAX: 086 664 4202 INT: +27 (0)21 976-8129 To subscribe to the journal or change address, email elsabe@clinicscardive.com Full text articles available on: www.diabetesjournal.co.za via www.sabinet.co.za The opinions, data and statements that appear in any articles published in this journal are those of the contributors. The publisher, editors and members of the editorial board do not necessarily share the views expressed herein. Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information. 22 VOLUME 20 NUMBER 2 • NOVEMBER 2023
VOLUME 20 NUMBER 2 • NOVEMBER 2023 23 SA JOURNAL OF DIABETES & VASCULAR DISEASE FROM THE EDITOR’S DESK From the Editor’s Desk Correspondence to: FA Mahomed Head of Internal Medicine, Madadeni Hospital Newcastle, KwaZulu-Natal Continued on page 28 CALSAR 5/80 mg, 5/160 mg, 10/160 mg. Each tablet contains amlodipine/valsartan 5/80 mg, 5/160 mg, 10/160 mg respectively. S3 A51/7.1.3/1106, 1107, 1108. For full prescribing information, refer to the professional information approved by SAHPRA, March 2021. CRB958/08/2022. CUSTOMER CARE LINE +27 21 707 7000 www.pharmadynamics.co.za | | | DILIGENT WORKERS BIOEQUIVALENT TO THE ORIGINATOR VALSARTAN/AMLODIPINE CONVENIENTLY PACKED IN 30 TABLETS Painkillers linked to heart failure in type 2 diabetes: Danish study Patients with type 2 diabetes (T2D) who use short-term nonsteroidal anti-inflammatory drugs (NSAIDs) have a greater risk of being hospitalised for heart failure, particularly older patients with poorly controlled diabetes, according to a Danish registry study. Among more than 300 000 patients with T2D, short-term use of NSAIDs was linked to a relative 43% increased risk of a first-time heart failure hospitalisation in the subsequent 28 days (OR: 1.43, 95% CI: 1.27–1.63), reported Dr Anders Holt of Copenhagen University Hospital-Herlev Gentofte in Hellerup, Denmark, and colleagues. The most at-risk subgroups were patients 80 years and older (OR: 1.78, 95% CI: 1.39–2.28), those poorly managed as evidenced by elevated HbA1c levels and no or only one anti-diabetic drug (OR: 1.68, 95% CI: 1.00–2.88), and new NSAID users without previous prescriptions (OR: 2.71, 95% CI: 1.78–4.23). ‘Individual risk assessment is advised if prescribing NSAIDs for patients with T2D,’ the researchers wrote in the Journal of the American College of Cardiology. NSAIDs have previously been linked to heart failure risk, doubling the risk of hospitalisations in one study, in a post-myocardial infarction population. Implications While the findings in T2D might not be surprising, they are worrying, given the widespread use of NSAIDs, according to an accompanying editorial by Dr Hassan Khan of Norton Healthcare in Kentucky, and Dr Setor Kunutsor, of the University of Leicester in England. This issue covers mainly cardiac issues, ranging from coronary arterial bypass grafting (CABG) outcomes to cardiovascular benefits of the latest diabetes drugs, the role of exercise in diabetes and arrythmias. CABG superiority over percutaneous coronary intervention (PCI) in diabetes has been shown in many studies. Early complications of CABG are bleeding, arrythmias and rehospitalisation.1 Yücel and Özgöl (page 24) studied early renal outcomes after CABG and found early adverse renal complications in patients with diabetes and low cardiac ejection fraction. Diabetes remainsamajorglobal riskfactor for cardiovasculardeath,2 and there is a great need to have drugs that treat hyperglycaemia and have cardiovascular benefit. Maney and Hanmonth (page 29) review the cardiovascular benefits of new diabetes drugs: sodiumglucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. The Diabetes News section stresses the importance of exercise in people living with diabetes (page 34). Exercise plays an important role in preventing obesity and diabetes,3 and also in improving diabetes control.4 Even modest exercise has benefit. This section also discusses the potential mechanisms of increased risk of arrhythmia in patients with diabetes (page 36). There appears to be a reduced risk of atria fibrillation in well-controlled diabetes and with treatment with the newer diabetes drugs. Atrial fibrillation is the commonest arrhythmia and requires rate control, anticoagulation and cardioversion strategies. This may require drugs or complex ablation interventions.5 References 1. Fearon WF, Zimmermann FM, De Bruyne B, Piroth Z, van Straten AHM, Szekely L, et al. Fractional flow reserve – guided PCI as compared with coronary bypass surgery. N Engl J Med 2022; 386(2): 128–137. 2. Magnussen C, Ojeda FM, Leong DP, Alegre-Diaz J, Amouyel P, et al. Global effect of modifiable risk factors on cardiovascular disease and mortality. N Engl J Med 2023; 389 (14): 1273–1285. 3. Hannon TS, Arslanian SA. Obesity in adolescents. N Engl J Med 2023; 389(3): 251–261. 4. Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med 2021; 384(18): 1719–1730. 5. Michaud GF, Stevenson WG. (2021). Atrial Fibrillation. N Engl J Med 2021; 384: 353–361.
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 24 VOLUME 20 NUMBER 2 • NOVEMBER 2023 Comparison of early postoperative results in patients with and without diabetes with low ejection fraction and normal serum creatinine values who underwent coronary artery bypass operation CIHAN YÜCEL, İLHAN ÖZGÖL Correspondence to: İlhan Özgöl Cihan Yücel Department of Cardiovascular Surgery, Prof Dr Cemil Taşçıoğlu City Hospital, Istanbul, Turkey e-mail: ilhanozgol@gmail.com Previously published online on 27 October 2023 in Cardiovasc J Afr S Afr J Diabetes Vasc Dis 2023; 20: 24–28 Abstract Background: Low left ventricular ejection fraction and renal insufficiency are factors that increase the risk of coronary artery bypass graft surgery in patients with diabetes mellitus. The aim of this study was to group patients with low left ventricular ejection fraction undergoing coronary artery bypass graft surgery according to the presence or absence of diabetes mellitus and to evaluate postoperative changes in serum creatinine levels and postoperative outcomes. Methods: A total of 93 patients undergoing isolated coronary artery bypass grafting were included in this singlecentre, retrospective, cohort study. Patients with a preoperative low left ventricular ejection fraction of less than 35% were included in the study. Patients were divided into diabetic and non-diabetic groups and intra- and intergroup values were compared. Pre-operative, and postoperative days 2 and 5 serum creatinine levels of the patients were measured and compared. Results: Of the 93 patients included in the study, 60 were in the diabetic group (group 1) and 33 were in the non-diabetic group (group 2). Postoperative 2- and 5-day creatinine levels were significantly higher in group 1 than in group 2 (p = 0.033 and p = 0.005, respectively). Postoperative 2- and 5-day creatinine levels were significantly higher than pre-operative creatinine levels in group 1 (p = 0.008 and p = 0.001, respectively). The intensive care unit stay was significantly longer in the diabetes mellitus group than in the group without diabetes mellitus (p = 0.031). Conclusion: Following coronary artery bypass graft surgery in patients with low left ventricular ejection fraction, which is already a risk factor, creatinine levels were found to have increased in the diabetes mellitus group. Keywords: cardiac surgery, acute kidney injury, diabetes mellitus, low left ventricular ejection fraction Coronary artery disease is one of the leading causes of death today.1 Percutaneous and medical treatment can be listed among the treatments for this disease, and surgical treatment also has an important place in ischaemic heart disease.2 Conditions such as low left ventricular ejection fraction (LLVEF < 35%), diabetes mellitus (DM) and renal failure are among the factors that increase mortality and morbidity rates in coronary artery bypass graft (CABG) surgery.1 Despite these risks, surgical treatment may be preferred to medical treatment because complete revascularisation can be achieved.3,4 Renal failure is a risk factor for CABG surgery, and CABG surgery and extracorporeal circulation are known to cause renal failure.5 Heart disease is associated with reduced renal function and progression of renal disease. The incidence of renal dysfunction after open-heart surgery is reported to be 30–50%, with 1–5% of these patients requiring permanent haemodialysis.6 DM is also a major risk factor for renal failure.7 CABG surgery in patients with LLVEF is associated with a risk of renal failure. In this study, we analysed the postoperative serum creatinine level changes in this group of patients and divided the patients with normal pre-operative creatinine values into two groups according to DM status. We also aimed to evaluate postoperative creatinine level changes and early postoperative outcomes in these groups. Methods All patients who underwent CABG surgery under cardiopulmonary bypass (CPB) in our clinic between 2019 and 2021 were retrospectively reviewed. The presence of coronary artery disease suitable for revascularisation on angiography and an LLVEF ≤ 35%, as calculated by two-dimensional echocardiogram, were the selection criteria for the study group. Patients with previous CABG, left ventricular aneurysm, coronary artery disease not suitable for CABG, moderate-tosevere mitral regurgitation, concomitant valvular heart disease, pre-operative creatinine value of 1.4 mg/ dl and above, and emergency and dialysis patients were excluded from this study. Patients with DMwere included in group 1 and those without DM (non-DM) were included in group 2. Demographic characteristics and pre- and postoperative data of the patients were compared. Local ethical approval was obtained from Prof Dr Cemil Taşçıoğlu City Hospital (number 2021/434). An informed consent form were obtained from the patients for this retrospectively designed study. Elective patients identified as CABG surgery candidates with a pre-operative creatinine level of less than 1.4 mg/dl were operated on under stable conditions. Patients were operated on at least two
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 20 NUMBER 2 • NOVEMBER 2023 25 weeks after the angiography procedure. Pre-operatively, immediately after cardiac catheterisation, the Nephrology Department was consulted and patients were hydrated under appropriate conditions. Patients did not take any regular nephrotoxic medication before or after the procedure. Basal creatinine concentrationwasmeasuredwithin the following seven days before surgery. After surgery, data were collected daily for seven consecutive days, including serum creatinine concentration and urine output. Urine output was measured at one-hour intervals during the first 72 hours postoperatively while the patient was in the post-operative care unit. The day of surgery was defined as day 0. Patients were assessed for the development of acute kidney injury (AKI) from postoperative day 1 to day 7, based on changes in serum creatinine concentration. Pre-operative creatinine levels, and post-operative day 2 and day 5 creatinine values were compared in groups 1 and 2, taking into account the minimum increase in creatinine concentration within 48 hours and one week, as in the acute kidney injury network (AKIN) and kidney disease improving global outcomes (KDIGO) criteria.8,9 Although the AKIN criterion seems to be more applicable than the KDIGO criterion, as it suggests a shorter time interval for the time of diagnosis, it was planned to look at day 5 creatinine values in addition to day 2 values, as this may underestimate the severity of AKI. Peri-operative outcomes were compared between the groups and post-operative complications were recorded. According to the AKIN classification, AKI was defined as an increase of ≥ 50% or 0.3 mg/dl in the pre-operative baseline creatinine level within 48 hours.9 Post-operative AKI was compared in both groups. All operations were performed on-pump by the same surgical team. There was no difference between coronary revascularisation techniques in the two groups. After releasing the left internal mammary artery, standard cannulation was performed, followed by antegrade cardioplegia cannula placement and CPB was initiated. Moderate hypothermia was maintained, and a roller pump and membrane oxygenator were used during CPB. The perfusion rate was set at 50–75 ml/kg/ min and mean arterial pressure at 60 mmHg and above. Myocardial protection was achieved with intermittent blood cardioplegia and topical cooling, following clamping of the aorta when appropriate conditions were provided. Distal anastomoses were made in crossclamps and proximal anastomoses were made in side clamps. Blood pressure, rhythm, amount of chest tube drainage, urine output, oxygenation profile, state of consciousness and pain control were closely monitored during intensive care unit (ICU) follow up. Mean arterial blood pressure was maintained at 60 mmHg and above by ensuring stable haemodynamics. Urine output was monitored hourly and blood gas, potassium and bicarbonate values were measured intermittently. Fluid support was provided so that urine output was 1 ml/kg/hour and above. The effect of crossclamps, total perfusion time and the number of bypass vessels on the change in postoperative creatinine value were investigated in both groups. Statistical analysis Analysis of the data was done in the IBM SPSS 22.0 (SPSS Inc, Chicago, IL, USA) package program. Descriptive statistics are shown as mean (standard deviation) for normally distributed variables and median (minimum – maximum) for non-normally distributed variables. The differences between the groups were evaluated with the t-test when the assumption of normal distribution was provided, and with the Mann–Whitney U-test when the assumption of normal distribution was not provided. The Spearman correlation test was used since the normality assumption was not provided for the relationship between continuous variables. Pearson’s chi-squared test was employed for intergroup comparison of categorical variables. For p < 0.05, the results were considered statistically significant. No sample calculation was made before the study. All patient records were accessed. Post hoc power analysis was performed with Gpower 3.1. The power was calculated as 0.69 for creatinine on postoperative day 2 and 0.84 for creatinine on postoperative day 5. Results A total of 93 patients with LLVEF ≤ 35% who underwent isolated CABG were analysed. Among these patients, 60 were in the group with DM (group 1) and 33 were in the non-DM group (group 2). The demographic characteristics of the patients are given in Table 1. The pre-operative LLVEF was found to be 32% (2.1) in group 1, and 31% (2.0) in group 2, and no statistically significant differences were found between the groups. There were no differences between the groups in terms of other demographic data. Although the peri-operative data of the patients (cross-clamp time, total perfusion time, number of bypass vessels) were numerically higher in group 1, this did not cause a statistically significant difference (Table 2). When comparing the two groups, no significant differences were found between the pre-operative creatinine values (p = 0.294). The postoperative creatinine values on days 2 and 5 were significantly higher in group 1 compared to group 2 (p = 0.033 and p = 0.005 respectively). Pre- and post-operative data are shown in Table 3. When both groups were evaluated, the post-operative creatinine levels at days 2 and 5 were significantly higher than the preoperative levels in group 1 (p = 0.008 and p = 0.001, respectively) (Fig. 1). Post-operative creatinine levels increased in group 2, but not to a statistically significant level (Table 4). The creatinine level increased above 2.0 mg/dl in two patients in the DM group on the second postoperative day. Since the urinary output was less than 0.5 ml/kg/hour, furosemide was given at a dose of 0.5 mg/hour for 12 hours in one patient and 24 hours in the other in order to provide cardiovascular stability. No patient required haemodialysis in the study groups. Table 1. Demographic characteristics of the groups DM group Non-DM group Demographics (n = 60) n (%) (n = 33) n (%) p-value* Age (years) 67.7 (9.9) 54.6 (6.3) 0.87 Gender Female 33 (55) 19 (57.5) 0.91 Male 27 (45) 14 (42.5) 0.94 Hypertension 18 (30) 10 (30.3) 0.80 BMI 27.0 (3.1) 26.71 (4.3) 0.61 COPD 15 (25) 8 (24.2) 0.44 Smoking 30 (50.0) 17 (51.5) 0.31 Ejection fraction 32 (2.1) 31 (2.0) 0.48 EuroSCORE (mean) 1.8 (0.6) 1.40 (0.4) 0.46 BMI: body mass index; COPD: chronic obstructive pulmonary disease, DM: diabetes mellitus. *Mann–Whitney U-test.
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 26 VOLUME 20 NUMBER 2 • NOVEMBER 2023 The incidence of AKI in the entire patient group was found to be 29%, according to the AKIN criteria. When comparing the patients who developed AKI in the two groups, 21 patients in group 1 and six patients in group 2 developed AKI. This difference was not statistically significant (p = 0.081) (Fig. 2). The correlation of cross-clamp times and total perfusion times with creatinine change was also examined in the study. In the DM group (group 1), a negative correlation was found between the postoperative creatinine increase on day 5 and the total perfusion time (R = –0.294, p = 0.023). The length of stay in the ICU was significantly longer in the DM group than in the non-DM group (p = 0.031). No patient required ultrafiltration in the peri-operative period. With the exception of erythrocyte suspension, no blood product was used in any of the patients in the pre-, intra- or postoperative period. The amount of post-operative drainage and the use of erythrocyte suspension did not differ between the groups (Table 3). One patient in the DM group developed a saphenous vein infection and three in each group developed atrial fibrillation. These patients returned to sinus rhythm with amiodarone treatment. No in-hospital mortality was observed in the study. Discussion DM is a common disease worldwide and is among the leading causes of cardiovascular diseases. It increases the risk of coronary artery disease and heart failure, and these conditions themselves may increase the risk of kidney failure. In addition, independently of these, DM itself can cause kidney failure. DM is responsible for approximately half of all end-stage renal disease in the United States of America.10 Approximately half of coronary artery disease patients also have DM.11 One of the main treatment options for coronary artery disease is CABG surgery. It has been found that 30% of patients undergoing Fig. 1. Within-group serum creatinine levels. Fig. 2. Intergroup acute renal disease. ARD: acute renal disease, DM: diabetes mellitus. Table 2. Peri-operative data DM group (n = 60) Non-DM group (n = 33) Mean Median Mean Median Peri-operative data (SD) (min–max) (SD) (min–max) p-value* Cross-clamp time 76.97 72 65.12 59 0.41 (min) (22.09) (43–115) (16.38) (44–109) Total pump time 123 113 119 112 0.81 (min) (29.2) (80–175) (24.3) (80–175) Bypass numbers 4.5 4.00 4.01 4.00 0.91 (0.5) (2–5) (0.7) (2–5) SD: standard deviation, min: minumum, max: maximum, DM: diabetes mellitus. *Mann–Whitney U-test. Table 3. Pre- and postoperative data DM group (n = 60) Non-DM group (n = 33) Pre- and post- Mean Median Mean Median operative data (SD) (min–max) (SD) (min–max) p-value* Pre-operative 1.02 1.05 1.03 0.95 0.294* creatinine (mg/dl) (0.17) (0.70–1.34) (0.18) (0.70–1.34) Postoperative day 2 1.28 1.26 1.11 1.0 0.033** creatinine (mg/dl) (0.37) (0.49–2.3) (0.35) (0.62–1.93) Postoperative day 5 1.24 1.36 1.07 1.09 0.005* creatinine (mg/dl) (0.34) (0.69–1.63) (0.24) (0.69–1.63) Drainage amount 568.78 574.98 514.48 500.00 0.279* (ml) (198.33) (450–630) (155.00) (450–650) Erythrocytes used 3.3 3 3.12 3 0.897* (0.12) (2–5) (0.14) (2–5) Length of stay in 3.65 4 3.12 3 0.031* ICU (day) (1.16) (2–6) (0.96) (2–5) Length of stay in 8.50 8 8.48 8 0.960* hospital (day) (1.93) (6–12) (1.5) (6–12) DM: diabetes mellitus, min: minimum, max: maximum, ICU: intensive care unit, SD: standard deviation.*Mann–Whitney U-test, **t-test. Table 4. Within-group serum creatinine levels via pre- and postoperative 2nd and 5th days Pre-operative Postoperative Postoperative creatinine (mg/dl) day 2 creatinine day 5 creatinine (P1) (mg/dl) (P2) (mg/dl (P5) Mean Median Mean Median Mean Median Groups (SD) (min–max) (SD) (min–max) (SD) (min–max) DM 1.02 1.05 1.28 1.26 1.24 1.36 (0.17) (0.70–1.34) (0.37) (0.49–2.3) (0.34) (0.69–1.63) Non-DM 1.03 0.95 1.11 1.0 1.07 1.09 (0.18) (0.70–1.34) (0.35) (0.62–1.93) (0.24) (0.69–1.63) DM group: P2 > P1, p = 0.008, P5 > P1, p = 0.001.
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 20 NUMBER 2 • NOVEMBER 2023 27 haemodilution, significant changes in intravascular volume, mechanical trauma to blood cells and more blood loss due to impaired coagulation status as a result of hypothermia.21 However, in the same study, although the number of patients who developed acute renal failure was higher in the on-pump group, no statistically significant difference was found between the two groups. In our study, there was no difference between the groups in terms of drainage and blood product replacement. Therefore, it is not possible to say that drainage and blood products were effective in terms of creatinine elevation in this study. Further studies with larger numbers of patients are needed. Changes in serum creatinine levels are the most widely used method of monitoring renal dysfunction.22 One of the major limitations of our study was that renal function was followed by only serum creatinine monitoring. More detailed studies on this topic are underway. The small number of patients and the inclusion of isolated CABG surgery patients are further limitations of this study. Conclusion It is well known that DM is one of the causes of kidney failure. This study showed that creatinine levels increased in the DM group after CABG surgery was performed in patients with LLVEF, which is also a risk factor for kidney failure. We believe that careful postoperative follow up in this group of patients could reduce the risk of permanent haemodialysis. It is predicted that minimal changes in creatinine levels after surgery, which means a small impairment in renal function, may have a negative effect on the outcome. Efficient follow up in the early postoperative period, recognising these changes, and taking precautions may lead to positive results. this operation have DM.12 DM, LLVEF and renal dysfunction are some of the most important factors that increase mortality and morbidity rates in patients undergoing CABG surgery. So what happens to patients with risk factors such as DM and LLVEF? There is a wealth of data that can be used to draw beneficial conclusions for patients. Guidelines recommend that CABG surgery should be performed in appropriate patients with the above risk factors, as total revascularisation can be achieved.13 As mentioned above, patients with LLVEF are at risk of renal failure, and CABG surgery in these patients increases this risk. It is well known that renal hypoperfusion and inflammatory damage caused by CPB via complex mechanisms are the causes of renal failure.5 The reported incidence of AKI associated with cardiac surgery varies between five and 42%, depending on the population studied.14 In patients undergoing CABG surgery, AKI developed in 26% of patients with LLVEF, and this is of course much more common in patients with DM.15 In the present study, serum creatinine levels were found to increase in the postoperative period in all patients undergoing CABG surgery in patients with pre-operative LLVEF < 35%. The study compared DM and non-DM control groups and although the percentage of AKI was numerically higher in the DM group, this did not reach statistical significance. However, there was a statistically significant increase in creatinine level change on days 2 and 5 postoperatively in the DM group. AKI is a common complication after cardiac surgery, prolonging ICU stay and hospitalisation.16 In their study of 1 881 patients undergoing open-heart surgery, Bastin et al.17 reported that AKI developed in 25.9% of patients, according to the AKIN classification. Sampaio et al.18 found that AKI developed in 51%, according to the AKIN classification. In the present study, the rate of AKI was found to be 29% in all patients, which is consistent with the literature. In addition, the length of stay in ICU was found to be statistically significantly longer in the DM group, with markedly higher serum creatinine levels than in the control group. This is also in line with the literature. Renal dysfunction and atrial fibrillation, which require balanced postoperative haemodynamics, fluid management, and good treatment and monitoring, were considered to be factors prolonging the ICU stay of patients in our study. DM is an independent risk factor for renal failure. The need for haemodialysis in the postoperative period, and mortality and morbidity associated with renal complications in diabetic patients ranged from28–63% in various studies andwere significantly higher than in non-DM patients.19 In the present study, the percentage of AKI was found to be higher in the DM group, in line with the literature. However, this rate was not statistically significant when compared to the control group. Cross-clamp times are prolonged in DM patients because of the high number of bypassed vessels. Although studies have shown a correlation between cross-clamp times and creatine elevation, no correlations were found between cross-clamp time and postoperative creatinine elevation in our study.20 We believe that the reason for this is the limited number of patients. Excessive amounts of blood transfusion, which is also considered to be tissue transplantation, causes more renal dysfunction and, of course, high morbidity and mortality rates. In a study comparing off- and on-pump CABG surgery, it was found that post-operative haematocrit levels were lower and amount of transfused blood products were higher in the on-pump group, associated with DYNA-PENTOXIFYLLINE SR. Each slow release tablet contains 400 mg pentoxifylline. S2 36/8/0282. NAM NS1 08/8/0183. For full prescribing information, refer to the professional information approved by SAHPRA, 11 December 2004. 1) Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline: meta-analysis of randomized controlled trials. CMAJ 1996 Oct 15;155(8):1053-9. DPEB1084/09/2023 CUSTOMER CARE LINE +27 21 707 7000 www.pharmadynamics.co.za solve a sticky situation Your cardiovascular patients face a dilemma. Hood SC, et al., reported that they can’t walk because of pain, but walking is exactly what they need to do.1 Oer them Dyna-Pentoxifylline SR 400 mg for the symptomatic relief of intermittent claudication, trophic ulcers and Raynaud’s syndrome.
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 28 VOLUME 20 NUMBER 2 • NOVEMBER 2023 References 1. Yamamuro M, Lytle BW, Sapp SK, et al. Risk factors and outcomes after coronary reoperation in 739 elderly patients. Ann Thorac Surg 2000; 69(2): 464–474. 2. Cooley DA. In memoriam. Tribute to René Favaloro, pioneer of coronary bypass. Texas Heart Inst J 2000; 27(3): 231–232. 3. Shapira OM, Hunter CT, Anter E, et al. Coronary artery bypass grafting in patients with severe left ventricular dysfunction – early and midterm outcomes. J Cardiac Sur 2006; 21(3): 225–232. 4. David G, Mario G, Juan G. The evolution of coronary bypass surgery will determine its relevance as the standard of care for the treatment for multivessel coronary artery disease. Circulation 2016; 134(17): 1206–1208. 5. Hashimoto K, Miyamoto H, Suzuki K, et al. Evidence of organ damage after cardiopulmonary bypass. The role of elastase and vasoactive mediators. J Thora Cardiovasc Surg 1992; 104(3): 666–673. 6. Zanardo G, Michielon P, Paccagnella A, et al. Acute renal failure in the patient undergoing cardiac operation. Prevalence, mortality rate, and main risk factors. J Thorac Cardiovasc Surg 1994; 107(6): 1489–1495. 7. Rahimi Z, Mansouri Zaveleh O, Rahimi Z, et al. AT2R – 1332 G: A polymorphism and diabetic nephropathy in type 2 diabetes mellitus patients. J Renal Injury Prevent 2013; 2(3): 97–101. 8. Kellum JA, Lameire N, Aspelin P, et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2(1): 1–138. 9. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care (London) 2007; 11(2): R31. 10. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med 1997; 14(Suppl 5): S1–S85. 11. Ali MK, Narayan KM, Tandon N. Diabetes and coronary heart disease: current perspectives. Indian J Med Res 2010; 132(5): 584–597. 12. Stallwood MI, Grayson AD, Mills K, et al. Acute renal failure in coronary artery bypass surgery: Independent effect of cardiopulmonary bypass. Ann Thorac Surg 2004; 77: 968–972. 13. Sousa-Uva M, Neumann FJ, Ahlsson A, et al. ESC Scientific Document Group. Eur J Cardiothorac Surg 2019; 55(1): 4–90. 14. Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol 2017; 13: 697–711. 15. Hertzberg D, Sartipy U, Lund LH, et al. Heart failure and the risk of acute kidney injury in relation to ejection fraction in patients undergoing coronary artery bypass grafting. Int J Cardiol 2019; 274: 66–70. 16. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351: 2795–2804. 17. Bastin AJ, Ostermann M, Slack AJ, et al. Acute kidney injury after cardiac surgery according to Risk/Injury/Failure/Loss/End-stage, Acute Kidney Injury Network and Kidney Disease: Improving Global Outcomes classifications. J Crit Care 2013; 28(4): 389–396. 18. Sampaio MC, Máximo CAG, Montenegro CM, et al. Comparison of diagnostic criteria for acute kidney injury in cardiac surgery. Arq Bras Cardiol 2013; 18–25. 19. Szabó Z, Håkanson E, Svedjeholm R. Early postoperative outcome and mediumterm survival in 540 diabetic and 2239 nondiabetic patients undergoing coronary artery bypass grafting. Ann Thorac Surg 2002; 74: 712–719. 20. Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, Abd Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel IU) Final Report. Circulation 2002; 106: 314–334. 21. Yusuf V, Mehmet I. Early-term outcomes of off-pump versus on-pump beating-heart coronary artery bypass surgery. Thorac Cardiovasc Surg 2019; 67(07): 546–553. 22. Wagener G, Jan M, Kim M, et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006; 105: 485–491. Several position statements already caution against both short- and long-term use of NSAIDs in patients at high cardiovascular risk, with the suggestion that use be of the shortest duration at the lowest dose that provides relief, the editorialists noted. Escalating that to a guideline recommendation would be ‘premature’, based on a single observational study, Khan and Kunutsor wrote. ‘Further robust clinical trial evidence is needed to replicate these results and investigate the relationship of the type and dose of NSAIDs with heart failure risk. However, it should be realised that short- or long-term use of NSAIDs may be detrimental to cardiovascular health.’ NSAIDs have potential cardiotoxic effects on fluid retention and blood pressure, but in this study, the five-year mortality risk after first-time heart failure hospitalisation was comparable for both NSAID-exposed and non-exposed patients, ‘suggesting that heart failure associated with the use of NSAIDs could be more than temporary fluid overload’, Holt and team wrote. Subgroup analysis turned up increased risk with poorly managed HbA1c levels but not among patients with normal HbA1c levels, independent of antidiabetic treatment intensity, which the researchers said ‘suggests that the combined effects of hyperglycaemia and NSAID exposure may lead to endothelial dysfunction, resulting in heart failure’, or ‘demasking’ subclinical heart failure caused by T2D. ‘However, the trend for stronger associations in subgroups with suspected compromised kidney function implies that both mechanisms (fluid overload and endothelial dysfunction) probably play important roles,’ they added. How they did it The study used nationwide Danish registers to identify all 331 189 adults (mean age 62 years, 44.2% women) diagnosed with T2D or started on antidiabetic medication from 1998 to 2021, who had no previous heart failure, rheumatic disease, or filled NSAID prescriptions 120 days before diagnosis. Type 1 diabetes patients and women under age 40 years who were only taking metformin (who might represent polycystic ovary syndrome rather than T2D) were excluded. While the primary associations examined were between NSAIDs and first-time heart failure hospitalisation using a case-crossover design with 28-day exposure windows, results were similar with 14- and 42-day windows. The study classified exposure as filled prescriptions for celecoxib, diclofenac, ibuprofen or naproxen – the main NSAIDs used in Denmark. Associations were similar for diclofenac and ibuprofen, but the results were insignificant for celecoxib and naproxen, possibly due to too few prescriptions filled. Of the 16% of patients who filled at least one NSAID prescription, ibuprofen was most common (12.2%), followed by diclofenac (3.3%), while naproxen and celecoxib prescriptions were each filled by less than 1% of patients. The few events that occurred after celecoxib and naproxen prescription limited the study’s ability to reliably explore for a class effect, the editorialists pointed out. ‘This is clinically relevant given that the various NSAIDs reversibly inhibit the enzyme cyclooxygenase (COX) in both of its isoforms, COX-1 and COX-2; however, their COX selectivity and associated cardiovascular risk vary,’ Khan and Kunutsor noted. ‘Evidence suggests that naproxen, a non-selective NSAID, is associated with the lowest risk of cardiovascular events, whereas diclofenac is associated with the highest cardiovascular risk among non-selective NSAIDs.’ Other limitations included the potential for time-varying and residual confounding and selection bias, as well as the fact that the researchers were only able to capture the short-term effects of transient exposures. In addition, the observational study could not establish a causal relationship. Source: MedicalBrief 2023 Continued from page 23
VOLUME 20 NUMBER 2 • NOVEMBER 2023 29 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW The cardiovascular benefits of new diabetes drugs Abstract Diabetes is associated with a significantly increased risk of cardiovascular disease. The emergence of novel antidiabetic medications not only aims to control blood glucose levels, but also shows the potential to mitigate the cardiovascular risks and long-term complications associated with the disease. The potential cardiovascular benefits and clinical implications of these antidiabetic drugs are examined in this article. The results of ongoing clinical trials and additional observational studies will further augment the development of newer drugs with added cardiovascular benefits and lead to more widespread use of these newer agents. This was a secondary analysis of various trials using new diabetes drugs, focusing on cardiovascular benefits and safety profile. Among these new antidiabetic drugs, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to be effective in reducing major adverse cardiovascular events. Conversely, dipeptidyl peptidase-4 inhibitors, although effective in controlling blood glucose levels, have not consistently shown significant cardiovascular benefits. Keywords: diabetes mellitus, cardiovascular disease, antidiabetic drugs, type 2 diabetes, chronic kidney disease, myocardial infarction, major adverse cardiovascular events SGLT2 inhibitors Diabetes is a chronic disease that affects millions of people worldwide and is a major cause of cardiovascular disease (CVD), which is the leading cause of death for diabetic patients.1,2 With the advent of new antidiabetic medications, significant progress in the treatment of diabetes has recently been made.3 It has been shown that the new antidiabetic drugs, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only help to regulate blood glucose levels but also provide cardiovascular benefits for diabetic patients.4-6 This research provides a summary of the potential cardiovascular benefits offered by newer antidiabetic drugs, shedding light on their clinical implications. SGLT2 is a low-affinity transporter located in the proximal renal tubules and responsible for glucose re-absorption.7 Essentially, SGLT2 inhibitors are pharmaceutical compounds that block SGLT2, leading to glucose elimination in the urine (Fig. 1).7,8 Common SGLT2 inhibitors, such as canagliflozin, dapagliflozin and empagliflozin, have been frequently used in conjunction with metformin to improve glucose control.9,10 Large-scale clinical trials such as the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 have shown that SGLT2 inhibitors can significantly reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes, including myocardial infarction (MI), stroke and cardiovascular death.10-12 Notably, empagliflozin reduced heart failure (HF) admissions, and this was a major change from the older generation hypoglycaemic medications that either were not beneficial or increased the incidence of HF (Table 1).13,14 In addition, SGLT2 inhibitors have also been proven in trials such as the EMPEROR-Reduced and DAPA-HF to lower the risk of HF hospitalisation and cardiovascular death in individuals with HF, irrespective of their diabetes status.15,16 Similarly, studies such as CREDENCE and DAPA-CKD have revealed that SGLT2 inhibitors can slow the progression of chronic kidney disease (CKD), lower the risk of end-stage renal disease, and even enhance renal outcomes in both diabetic and non-diabetic individuals (Table 1).17 A collective meta-analysis of the DAPA-HF and DELIVER trials indicated that dapagliflozin reduced the risk of cardiovascular death, hospitalisation for HF and MACE across a range of left ventricular ejection fractions of 25 to 65%.15,18 However, trial results did reveal some known adverse effects of SGLT2 inhibitors (Table 1). Those who received canagliflozin had an increased risk of amputation, specifically at the toe or metatarsal.19 Canagliflozin should be avoided by patients at higher risk for amputation, according to the American Food and Drug Administration (FDA).19,20 Since canagliflozin induces glycosuria, the incidence of superficial genital mycotic infections is common, especially in women and uncircumcised men.21 In addition, their use is linked to an increased risk of urinary tract infection and euglyacemic diabetic ketoacidosis.20,22 A MANEY, K HANMONTH Correspondence to: A Maney Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa e-mail: avishkarmaney@gmail.com K Hanmonth Charlotte Maxeke Academic Hospital, Johannesburg, South Africa S Afr J Diabetes Vasc Dis 2023; 20: 29–33 Fig. 1. Mechanism of action of SGLT2 inhibitors.23
30 VOLUME 20 NUMBER 2 • NOVEMBER 2023 REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE DPP-4 inhibitors The next class of drugs are the dipeptidyl peptidase-4 (DPP-4) inhibitors. These are oral antidiabetic agents that block incretin degradation by DPP-4, thereby inhibiting breakdown of GLP-1, the gastric inhibitory peptide, and other incretins, leading to postprandial insulin release (Fig. 2).24,25 The commonly used agents in this class are saxaglipitin, aloglipitin and sitaglipitin. These drugs exhibit modest glycated haemoglobin (HbA1c) reductions while posing minimal risks of hypoglycaemia and weight gain.24 DPP-4 inhibitors have been widely used because of their notable safety profiles, minimal risk of hypoglycaemia and good tolerability. However, cardiovascular outcome trials (CVOTs) have failed to demonstrate a significant prognostic advantage.24-26 Clinical trials with three of these agents, saxaglipitin, aloglipitin and sitaglipitin Table 2. Summary of DPP-4 inhibitors Benefit Outcome Study name outcome Study hazard and drug measure design ratio (HR) Reference SAVOR-TIMI CV death, non- T2D patients CV death: HR = 46 53 fatal MI, with either a 1.16, p = 0.66 Saxagliptin or non-fatal history of MI: HR = 1.12, ischaemic recognised p = 0.52 stroke CVD or with Stroke: HR = multiple risk 1.11, p = 0.38 factors for vascular disease EXAMINE Time to first T2D adults CV death 48 Alogliptin occurrence of with high CV overall: HR = non-fatal and renal 0.96, p = 0.62 MI or non-fatal risk MI overall: HR stroke = 1.12, p = 0.30 Stroke overall: HR = 0.92, p = 0.53 TECOS First confirmed T2D patients > Primary 49 Sitagliptin event of CV 50 years, with outcome: 0.98, death, non-fatal established p < 0.001 MI, non-fatal CVD Secondary stroke or outcome: 0.99, hospitalisation p < 0.001 for unstable angina (primary outcome) Secondary outcome: CV death, non-fatal MI or non-fatal stroke CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; ACS, acute coronary syndrome. Table 1. Summary of SGLT-2 inhibitors Benefit Inclusion Study name outcome Outcomes and hazard and drug measure criteria ratio (HR) Reference EMPA-REG Death from CV CV events in Reduced death 50 OUTCOME causes, non-fatal adults with from CV cause: Empagliflozin myocardial T2D at high HR = 0.66, p = infarction, or risk 0.001 non-fatal stroke Death rate and HF hospitalisations: HR = 0.61, p = 0.001 CANVAS A composite of T2D patients > Reduced death 51 Canaglifozin death from CV 50 years with > from CV cause: causes, non-fatal two CVD risk HR = 0.86, p < MI or non-fatal factors or > 30 0.001 for non- stroke years with a inferiority history of Hospitalisation symptomatic rate for HF: HR = atherosclerotic 0.68 95% CI: CV disease 0.51–0.90 DAPA-HF Worsening HF or Adults with an CV outcomes 51 Dapagliflozin death from CV ejection fractionreduction: HR = causes ≤ 40%, and 0.74, p = 0.001 NYHA class II–IV EMPEROR - Time to first Chronic HF Reduced CV 52 Reduced event of CV (NYHA class II– death: Empagliflozin death or IV) and reduced HR = 0.75, hospitalisation ejection fraction p = 0.001 for HF and elevated NT-proBNP levels CREDENCE A composite of CKD patients CV death: HR = 15 Canagliflozin doubling of (eGFR 30–90 0.78 p = 0.05 serum creatinine ml/min/1.73 Doubling of levels from m2 and urinary serum creatinine: baseline, end- ACR 300– 0.60 mg/dl, p = stage kidney 5 000 mg/g 0.001 disease or death End-stage renal from CV or renal disease: 0.68, p = disease 0.002 DECLARE- MACE (CV T2D patients CV death or 52 TIMI 58 death, MI or with multiple reduction in HF Dapagliflozin ischaemic risk factors for hospitalisations: stroke) ASCVD HR = 0.83, p = (10 186) 0.005 or established ASCVD (6 974) CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; HF, heart failure; NYHA, New York Heart Association; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ACR, albumin to creatinine ratio; MACE, major adverse cardiovascular events; ASVD, atherosclerotic cardiovascular disease; ACS, acute coronary syndrome. Fig. 2. Flow diagram showing the mechanism of DPP-4 and GLP-1 analogues.
VOLUME 20 NUMBER 2 • NOVEMBER 2023 31 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW (SAVOR-TIMI 53, EXAMINE and TECOS, respectively), showed that when compared to a placebo, these drugs did not increase the risk of MACE or overall mortality. However, there were no significant cardiovascular benefits associated with their use (Table 2).27 Saxaglipitin was associated with an increased incidence of HF hospitalisations, according to SAVOR-TIMI 53.28 The most common side effects observed with sitagliptin and saxagliptin were headache, nasopharyngitis, arthralgia, and urinary and upper respiratory tract infections.29 Other side effects, although rare, included hypersensitivity responses, notably anaphylaxis and angiooedema. Pancreatitis and Stevens-Johnson syndrome have been reported in a few cases.28,29 GLP-1 receptor agonists The final class of newer antidiabetic agents reviewed in this article are the GLP-1 RAs. GLP-1 is a hormone that stimulates glucosedependent insulin release from the pancreatic islets.30 GLP-1 has an incretin effect, delaying gastric emptying and inhibiting inappropriate post-meal glucagon release and reduced food intake (Fig. 2).31 Patients with type 2 diabetes have an impaired insulin response to GLP-1, which is hypothesised to be related to a reduction in postprandial GLP-1 secretion.32 GLP-1 RAs stimulate GLP-1 receptors, leading to insulin secretion and decreased glucagon secretion.33 Trials using GLP-1 RAs have shown a significant reduction in MACE, however, there is conflicting evidence on their benefits in patients with HF and CKD.34 The LEADER trial in 2016 and the REWIND trial in 2019 evaluated liraglutide and dulaglutide, respectively, and indicated that there was a relative reduction in MACE with the use of both these drugs.35 Semaglutide was evaluated in the SUSTAIN trial and showed a reduction in MACE, CKD progression and total stroke in patients.36 The evaluation of this drug in the PIONEER 6 trial, however, showed that oral semaglutide did not reduce MACE (Table 3).37 Current guidelines support the use of dulaglutide, liraglutide and semaglutide (injectable, not oral) for reduction of ischaemic events in patients with type 2 diabetes.36,38 The most recent trial is the SELECT trial that evaluates the cardiovascular effects of semaglutide on overweight or obese patients with prior cardiovascular disease. The trial completion date was the end of September 2023.39 The potential side effects encountered with the use of these agents are important to note whenever prescribing these agents, and could lead to discontinuation of use. Gastrointestinal discomforts such as nausea, bloating and abdominal pain are noted as common side effects, and this is a leading cause of treatment discontinuations.40 The more serious side effects of GLP-1 RAs are pancreatitis and pancreatic cancer.40 Transient tachycardia may result from stimulation of GLP-1 receptors found in the sino-atrial node, most likely due to β-adrenergic stimulation and subsequent vasodilation.41 Since the 2008 FDA regulations, numerous CVOTs have shown not only the cardiovascular safety of new antidiabetes medications but also cardiovascular benefits to patients. SGLT2 inhibitors and GLP-1 RAs caused a significant reduction in fatal and non-fatal ischaemic events among patients with diabetes and atherosclerotic CVD.42 SGLT2 inhibitors have been shown to reduce hospitalisations and mortality in HF patients as well as slowing CKD progression.10,11 DPP-4 inhibitors have been shown to be inferior to GLP-1 RAs and SGLT2 inhibitors and cardiovascular outcomes have not been observed with their use.43 The American Diabetes Association 2020 has recommended metformin as the first-line agent for type 2 diabetes.44 In patients with the risk of atherosclerotic CVD, GLP-1 RAs are the preferred choice, and for patients with CKD or HF, the preferred choice is SGLT2 inhibitors. For those patients without risk factors or established CKD/CVD or HF, any of the DPP-4 inhibitors, GLP-1 RAs, SGLT2 inhibitors or sulphonylureas can be used.44 The European Society of Cardiology 2019 guideline recommends the first-line option for CVD or high cardiovascular risk is SGLT2 inhibitors, and GLP-1 RAs are recommended with metformin for low cardiovascular risk.45 Despite the recommendations, the real-world uptake of the newer agents remains limited, especially outside endocrinology Table 3. GLP-1 receptor analogues Benefit Outcome Study name outcome Inclusion hazard and drug measure criteria ratio (HR) Reference LEADER Death from CV Patients with Primary 35 Liraglutide causes, non-fatal T2D > 50 outcome: HR = MI, or non- years with 0.87, p = 0.01 fatal stroke established CV death: HR = (primary CVD, CKD 0.85, p = 0.007 composite stage 3 or Non-fatal stroke outcome) higher or > 60 = 0.89, p = 0.30 years with one or more CVD risk factors HARMONY Death from CV T2D with The primary 53 OUTCOMES causes, MI and HbA1c > 7.0% outcome, CV Albiglutide stroke and > 40 death, non-fatal years, with MI or stroke, established HR = 0.78, p < coronary 0.0001 cerebrovascular or peripheral arterial disease EXSCEL Primary Patients with Primary 54 Exenatide outcome: first T2D at any outcome: occurrence of level of CV HR = 0.91, death from CV risk, including p = 0.001 causes, non- established fatal MI or CV disease non-fatal stroke REWIND Primary T2D patients > Primary 54 Dulaglutide outcome: first 50 years, with outcome: episode of either previous HR = 0.88, non-fatal MI, CV risk factors p = 0.026 non-fatal or event stroke, and death from CV or unknown causes PIONEER 6 MACE, Patients ≥ 50 MACE: HR = 37 Semaglutide consisting of years with 0.79 p < 0.001 death from CV established CV death: HR = causes (undeter- CV or CKD, 0.49, 95% CI: mined causes or ≥ 60 years 0.27–0.92 included), non- with CV Non-fatal MI, fatal MI or non- risk factors HR = 1.18. 95% fatal stroke only CI: 0.73–1.90 CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; ACS, acute coronary syndrome.
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