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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 19 NUMBER 2 • November 2022 www.diabetesjournal.co.za CONTENTS 23 From the Editor’s Desk FA Mahomed Research Article 24 Impact of diabetes mellitus on the frequency of post-operative complications after carotid endarterectomy GL Igrutinović, DD Nenezić, AR Jakovljević, ZN Elek, NM Miljković, MN Kasalović, DR Vićentijević Review 29 The use of fenugreek in ameliorating hyperglycaemia and diabetes C Mohan Opinion Piece 32 Diabetes and heart disease G Makan
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. 16 VOLUME 19 NUMBER 2 • November 2022 Learning to live with diabetes 33 Diabetes is not just about sugar, every organ is affected Joy Steenkamp Diabetes News 35 Dairy products may protect against type 2 diabetes: Italian meta-analysis 36 Canada’s ‘pioneering’ guidelines on adult obesity 37 World Diabetes Day ‘Education to protect tomorrow’ 38 BMI strongly associated with all-cause mortality 39 Low-fat, plant-based diet to low-carb, animal-based diet compared 40 Stringent diet puts diabetes into remission and cuts need for blood pressure medication CONTENTS
VOLUME 19 NUMBER 2 • November 2022 3 SA JOURNAL OF DIABETES & VASCULAR DISEASE From the Editor’s Desk Correspondence to: FA Mahomed Head of Internal Medicine, Madadeni Hospital Newcastle, KwaZulu-Natal Happy Holidays we wish you joy A warm thank you from the management and staff of Clinics Cardive Publishing (publishers of the Cardiovascular Journal of Africa and the South African Journal of Diabetes & Vascular Disease) to our authors, reviewers and clients for your continued support and collaboration. May your holiday season and the new year be filled with much joy, happiness, health and success. Our office will close on 15 December 2021 and open on Monday 16 January 2022. We look forward to being of service to you in the new year. From the Editor’s Desk This issue of the journal looks at a range of topics, including a view on complications after carotid endarterectomy, the use of herbs in diabetes, an article on diabetes and heart disease, as well as news items that cover the impact of dairy products on diabetes, obesity and plant-based diets. Igrutinovic et al. (page 24), from Dedinje Clinic in Belgrade, examined complications after carotid endarterectomy in patients with and without diabetes. They show a clear increase in cardiac and neurological complications in patients with diabetes. Other studies show little difference in morbidity and mortality and overall safety of the procedure.1 Mohan (page 29) reviews published articles on the effectiveness of fenugreek in diabetes. The use of plants in medicine has a long history and insights like these are always fascinating. Read the article to get the answer about its effectiveness. Makan (page 32) from Life Wilgeheuwel puts cardiovascular assessment in diabetes into perspective. Use of coronary artery calcium scores, ECG stress testing, radionuclide cardiac tests, and others, remain options, but their use in screening for cardiovascular disease in diabetes is still being debated.2 Steenkamp presents a useful patient-friendly article explaining diabetes. A meta-analysis from the University of Naples (page 35), presented at the EASD, shows the benefit of dairy products in diabetes. While there is considerable interest in the impact of dairy products, it seems that the studies show that the overall effect on diabetes is neutral to mildly beneficial.3 The Canadian approach to management of obesity indicates that a holistic, life-long approach might be best (page 36). A study on body mass index and mortality is also discussed (page 38). Obesity remains a problem of our time and statistics show a relentless increase in obesity rates. Morbidity and mortality will weigh heavily on government’s health budgets.4 References 1. Rockman CB, Saltzberg SS, Maldonado TS, Adelman MA, Cayne NS, Lamparello PJ, et al. The safety of carotid endarterectomy in diabetic patients: clinical predictors of adverse outcome. J Vasc Surg 2005; 42(5): 878–883. 2. https://www.acc.org/guidelines. Accessed 13/12/2022. 3. Guo J, Givens DI, Astrup A, Bakker SJL, Goossens GH, Kratz M, et al. The impact of dairy products in the development of type 2 diabetes: where does the evidence stand in 2019? Adv Nutr 2019; 10(6): 1066–1075. 4. https://www.cdc.gov/obesity/data/adult.html. Accessed 13/12/2022.
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 24 VOLUME 19 NUMBER 2 • November 2022 Impact of diabetes mellitus on the frequency of postoperative complications after carotid endarterectomy Correspondence to: Gojko Lj Igrutinović, Gojko Lj Igrutinović, Aleksandar R Jakovljević, Nikola M Miljković, Mladen N Kasalović, Surgery Clinic, Kosovska Mitrovica Clinical Hospital Centre, Kosovska, Mitrovica, Serbia e-mail: drgojkoigrutinovic@gmail.com Dragoslav Dj Nenezić, Institute for Cardiovascular Diseases, Dedinje, Belgrade, Serbia Zlatan N Elek, Danijela R Vićentijević Medical Faculty, Kosovska, Mitrovica, Serbia S Afr J Diabetes Vasc Dis 2022; 19: 24–28 Stenotic occlusive diseases of the carotid arteries are some of the most frequent surgical vascular diseases, and the incidence is increasing, and carotid endarterectomy (CEA) is the most frequent operation carried out at vascular surgery clinics.1 It is well known Gojko Lj IgrutinoviC, Dragoslav Dj NeneziC, Aleksandar R JakovljeviC, Zlatan N Elek, Nikola M MiljkoviC, Mladen N KasaloviC, Danijela R ViCentijeviC ` ` ` ` ` ` ` Abstract Background: There is significant controversy surrounding the link between diabetes mellitus and post-operative complications after carotid endarterectomy (CEA). The aim of this study was to identify the possible effects of diabetes on the frequency of post-operative complications after CEA. Methods: This prospective study was conducted at the Dedinje Clinic for Vascular Surgery, Belgrade. The patients who underwent CEA were divided into two groups: group A (37.7%) included 98 (35.1%) insulin-dependent and 181 (64.9%) insulin-independent diabetic patients, and group B (62.3%) comprised non-diabetic subjects. Results: The pre-operative characteristics were similar, except for a greater prevalence of dyslipidaemia in patients with diabetes. Post-operative cardiac events occurred more often in patients with diabetes (3.6%) than in non-diabetic patients (1.1%) (p = 0.039); post-operative neurological events among patients with diabetes were 3.6% and among non-diabetics, 0.9% (p = 0.009). Peri-operative mortality rate was 2.5% in the diabetic group and 0.9% in the nondiabetic group. The total percentage of post-operative complications was two or more times higher in the diabetic group than the non-diabetic group (8.5 vs 18.3%, p < 0.001). Conclusions: Diabetes mellitus increased the surgical risk of CEA. Higher rates of mortality and post-operative complications were observed in patients being treated with oral antidiabetics than in those on insulin. Keywords: carotid endarterectomy, diabetes mellitus, postoperative complications that diabetes mellitus (DM) is a progressive disease that significantly contributes to degradation of atherosclerotic plaques in the arteries.2 CEA represents the first choice of treatment of high-level carotid stenosis and carries a low rate of post-operative morbidity and mortality.3 According to the literature, the percentage of patients with DM within the group of patients who undergo CEA has been on the rise, ranging from 10% to over 25%.4,5 On the other hand, diabetes is an important risk factor for the occurrence of myocardial infarction (MI) and stroke in the general population, and it can also impact on the outcome of CEA.6 Some authors believe that patients suffering from DM are at up to two times greater risk of overall post-operative complications compared to patients with no diabetes.6-8 On the other hand, others have observed that patients suffering from DM were exposed to the same risk of cardiological morbidity, mortality and stroke after CEA as patients with no diabetes.9-11 It has been proven that there is a risk of stroke in diabetic patients and it is related to the level of hyperglycaemia; it is assumed that controlled glycaemia may lower the risk of stroke.12 Since most of these studies have not taken into consideration the type of antidiabetic therapy, this could explain the contradictory results among studies on the influence of DM on the outcome of CEA. The aim of this article was to determine the frequency of post-operative complications after CEA in patients with or without DM, as well as to identify the type of antidiabetic therapy, in order to define the safety of the operation concerned. Methods This prospective, non-randomised study included all patients treated at the Institute for Cardiovascular Diseases, Dedinje, Belgrade, who, in the time period from December 2013 to December 2014, underwent CEA, and were entered into the prospective vascular registry. The patients were divided into two groups: group A (37.7%) consisted of 279 diabetic patients, including 98 (35.1%) being insulin-dependent and 181 (64.9%) taking oral hypoglycaemics. Group B (62.3%) consisted of 461 non-diabetics. A complete comparison of demographic characteristics and risk factors was done (gender, age, hypertension, hyperlipidaemia, smoking, pre-operative MI, concomitant vascular diseases). After the operation we compared post-operative complications [transient ischaemic attack (TIA), cerebrovascular infarction (CVI), MI, neurological, cardiological and other morbidities, and total mortality rate]. Control colour duplex sonography (CDS) of the carotid artery was carried out one month, six months and one year later. Our primary goal was 30-day morbidity and mortality, which is defined as any death or post-operative morbidity within 30 days of the treatment,
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 19 NUMBER 1 • July 2022 25 as well as a percentage of carotid restenosis up to one year postoperatively. Indication for CEA was set after CDS of the carotid artery and multislice (MSCT) angiography of supra-aortic branches. Carotid stenosis was ascertained according to the European carotid surgery trial (ECST) criteria, as well as by means of the criteria described by AbuRahma et al.13 Carotid stenosis was defined as significant (> 70% constriction) if systolic velocity was > 150 cm/s and diastolic velocity > 90 cm/s. Peri-operative neurological morbidity was classified as TIA lasting less than 24 hours or permanent stroke (deficiency present on discharge). An adverse post-operative cardiac event has been designated as a post-operative MI and congestive heart failure (CHF). Post-operative restenosis was defined as ultrasound-verified stenosis of the carotid artery on the operated side as larger than 50%. Patients with a history of disease of the coronary artery underwent stress tests and, in some cases, coronarography. Peripheral vascular disease was proven by means of CDS of the lower extremities and, if deemed necessary, using angiography. For evaluation of pre-operative neurological disorders, as well as post-operative neurological condition, a modified scale of Rankin scores was used, with a neurological damage estimate ranging from 0 to 5.14 The patients were operated on under general endotracheal anaesthesia. The CEA eversion technique was applied on all patients. All patients with post-operative complications underwent a computed tomography (CT) of the endocranium post-operatively. Statistical analysis The testing of statistical hypotheses made use of the t-test for two independent samples, Mann–Whitney test, chi-squared test and Fisher’s test of accurate probability. Logistic regression was used for analysing the relationship between binary outcomes and potential predictors. Statistical hypotheses were tested at the level of statistical significance (alpha level) of 0.05. Results The main characteristics are shown in Table 1. Group A (37.7%) consisted of 279 diabetic patients and group B (62,3%) comprised 461 non-diabetic subjects. Except for a slightly higher prevalence of dyslipidaemia in patients with diabetes (χ2 = 5.330; p = 0.021), patients with DM had more frequent coronary artery disease (χ2 = 15.090; p < 0.001) and more persistent peripheral arterial disease (χ2 = 20.607; p < 0.001). Other pre-operative characteristics for the two groups were similar and comparable. Post-operative complications are shown in Table 2. Neurological events (TIA) among patients with diabetes were 3.6% and among Table 1. Pre-operative characteristics of diabetics and non-diabetics Group A: Group B: diabetics non-diabetics Characteristics 279 (37.7%) 461 (62.3%) p-value Average age 67.5 ± 7.2 66.8 ± 7.5 NS Male, n (%) 165 (59.1) 278 (60.3) NS Female, n (%) 114 (40.9) 183 (39.7) NS Smoking, n (%) 169 (95.7) 257 (92.4) NS Hypertension, n (%) 267 (61.3) 426 (64.4) NS Dyslipidaemia, n (%) 265 (95.0) 416 (90.2) 0.021 Concomitant coronary disease, n (%) 89 (31.9) 89 (19.3) < 0.001 Concomitant peripheral disease, n (%) 70 (25.1) 56 (12.1) < 0.001 Previous MI, n (%) 38 (13.6) 30 (6.5) 0.001 Previous TIA, n (%) 10 (3.6) 4 (0.9) NS Previous CVI, n (%) 9 (3.2) 6 (1.3) NS Positive CT of endocranium 12 (4.66) 10 (2.17) NS MI, myocardial infarction; TIA, transient ischaemic attack; CVI, cerebrovascular incident. Table 2. Post-operative complications in diabetics and non-diabetics after CEA Group A: Group B: Characteristics diabetics non-diabetics p-value Post-operative TIA, n (%) 10 (3.6) 4 (0.9) 0.009 Post-operative CVI, n (%) 9 (3.2) 6 (1.3) 0.072 CT ischaemic brain lesion, n (%) 11 (3.94) 8 (1.74) 0.424 Cranial nerves lesion, n (%) 2 (0.7) 4 (0.9) NS Myocardial infarction, n (%) 2 (0.7) 1 (0.2) 0.300 Congestive heart failure, n (%) 8 (2.9) 4 (0.9) 0.039 Post-operative respiratory complications, n (%) 8 (2.9) 3 (0.7) 0.024 Haematoma of operated wound, n (%) 10 (3.9) 11 (2.4) 0.341 Infection of operated wound, n (%) 5 (1.8) 0 (0.0) 0.007 Post-operative 50% restenosis, n (%) 5 (1.8) 10 (2.2) 0.724 TIA, transient ischaemic attack; CVI, cerebrovascular incident. BILOCOR 5, 10. Each tablet contains 5, 10 mg bisoprolol fumarate respectively. S3 A38/5.2/0053, 0051. NAM NS2 06/5.2/0061, 0062. For full prescribing information, refer to the professional information approved by SAHPRA, 23 July 2010. BILOCOR CO 2,5/6,25, 5/6,25, 10/6,25. Each tablet contains 2,5, 5, 10 mg bisoprolol fumarate respectively and 6,25 mg hydrochlorothiazide. S3 A44/7.1.3/1010, 1011, 1012. NAM NS2 13/7.1.3/0260, 0261, 0262. For full prescribing information, refer to the professional information approved by SAHPRA, 06 May 2019. BRF838/05/2022. www.pharmadynamics.co.za CUSTOMER CARE LINE +27 21 707 7000 Let the ßeat go on
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 26 VOLUME 19 NUMBER 2 • November 2022 non-diabetics (0.9%) (p = 0.009). Post-operative CVI occurred in 1.3% of patients without diabetes and in 3.2% of patients with diabetes (χ2 = 3.241; p = 0.072). Cumulative neurological events TIA/cerebrovascular infarction were also statistically more numerous in the diabetic group (p = 0.02). Adverse post-operative cardiac events (MI, CHF) occurred in 3.6% of patients with diabetes and in 1.1% of non-diabetic patients (Fisher’s test of accurate probability; p = 0.039). Haematoma of the surgical wound occurred in 11 patients (2.4%) without DM and in 10 patients (3.6%) with DM, which was statistically significantly different (χ2 = 0.905; p = 0.341). Infection of the operated wound in our study was present in 1.8% of patients with DM, while none of the patients without DM had wound infection, which was statistically significant (Fisher’s test of accurate probability; p = 0.007). We observed that 0.9% of non-DM patients and 0.7% of DM patients had symptoms of cranial nerve lesions, which was statistically insignificant (Fisher’s test of accurate probability; p = 1.000). Post-operative restenosis occurred in 2.2% of patients without DM and in 1.8% of those with DM. The total rate of complications, shown in Table 3, was within the recommended limits. With regard to the rates of mortality and total morbidity, the two groups differed considerably from one another. Operative and post-operative mortality (neurological and cardiological) was 2.5% in the diabetic group (four cardiac events and three cerebrovascular infarctions) and 0.9% in the nondiabetic group (three MIs and one cerebrovascular infarction) (p = 0.113). The patients with DM had statistically significantly higher total mortality rates. Total post-operative complications were observed in 8.5% of patients without DM and in 18.3% of patients with DM (χ2 = 15.688; p < 0.001). Post-operative complications occurred in DM patients considerably more frequently (two or more times). One hundred and eighty-one DM patients (64.9%) were using oral antidiabetics and 98 (35.1%) were on insulin. Total postoperative complications occurred in 25.4% of patients on oral antidiabetics and in 8.2% of patients on insulin (χ2 = 12.122; p < 0.001). Post-operative complications occurred in patients on oral antidiabetics considerably more frequently than in those using insulin (Table 4). The stratification of patients with diabetes according to their levels of glycosylated haemoglobin (HbA1c) has shown that the group with HbA1c levels > 7.6 % had a higher total morbidity and mortality rate (Table 5). The median value of HbA1c in patients without post-operative complications was 7.6 ± 1.2, whereas the median value of HbA1c in patients with post-operative complications was 8.4 ± 0.9 (t = 5.010; p < 0.001). Patients with post-operative complications had significantly higher values of HbA1c. The multiple logistic regression model, with post-operative complications as a dependent variable, was supplemented with those predictors of post-operative complications that were statistically significant in the simple logistic regression model, the significance level being 0.05. Statistically significant predictors of early post-operative complications in the multiple logistic regression model were: age (B = 0.069; < 0.001) with odds ratio (OR) = 1.07, and it demonstrates that with increase in age of one year there is a 7% greater risk for patients to develop early post-operative complications. Diabetes (B = 0.854; p = 0.001) had an OR of 2.35, showing that diabetic patients were, with all other factors in the model controlled, at 2.35 times greater risk of the development of early post-operative complications. Concomitant coronary artery disease patients (B = 0.844; p = 0.001), (OR = 2.33) were at 2.33 times greater risk of the development of post-operative complications, with all other factors in the model controlled. With logistic regression, the factors identified to increase the odds of death and post-operative complications were: hyperlipoproteinaemia (p = 0.021), more persistent coronary artery disease (p = 0.001) and a higher frequency of peripheral arterial disease (p < 0.001). The factors determined to increase the odds of death and total morbidity were: higher levels of HbA1c (p < 0.001) and oral antidiabetics for controlling glucose levels (p < 0.001), which is shown in Tables 4 and 5. Discussion Although previous studies evaluated the connection between diabetes and a greater operative risk during CEA, there are various conflicting results in many studies. Most studies introduce CEA as a well-known and permanent procedure for the prevention of TIA and cerebrovascular infarction in patients with significant stenosis of the carotid artery.15 In previous studies, which included patients operated on for stenotic occlusive disease of the carotid arteries, the percentage of diabetics in most cases ranged from 13 to 23.6%.6,15 Our series included 37.7% of patients with diabetes, which is considerably higher compared to the study done by Ahari et al., which had 13% diabetic patients.5 Dorigo et al. report that the percentage of DM patients was 20.05%, whereas the study by Rockman et al. Table 3. Total mortality and morbidity rates in patients with diabetes and without diabetes who underwent CEA Group A: Group B: Structure of patients diabetics non-diabetics Total p-value Fatal cardiac event, n (%) 4 (1.4) 3 (0.7) 7 (0.9) 0.435 Fatal neurological event, n (%) 3 (1.1) 1 (0.2) 4 (0.5) 0.153 Total mortality, n (%) 7 (2.5) 4 (0.9) 11 (1.5) 0.113 Total morbidity, n (%) 51 (18.3) 39 (8.5) 90 (12.2) < 0.01 Table 5. HbA1c level in examined patients HbA1c level Number % SD Median Minimum Maximum Without post-operative 225 7.6 1.2 8.0 6.0 9.8 complications With post-operative 54 8.4 0.9 8.5 6.0 9.5 complications Total 279 7.8 1.2 8.0 6.0 9.8 Table 4. Distribution of patients depending on diabetes therapy, in relation to post-operative complications Oral antidiabetics Insulin therapy Total Post-operative complications n % n % n % Not present 135 74.6 90 91.8 225 80.6 Present 46 25.4 8 8.2 54 19.4 Total 181 100.0 98 100.0 279 100.0
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 19 NUMBER 2 • November 2022 27 reports 23.5%.6,9 The study done by Jeong et al. reports on a high percentage of diabetics in Asia, up to 39%.16 The high percentage of diabetics in our study can be explained by the fact that DM has been reaching epidemic proportions in the general population over the last two decades, and especially in the group of patients with atherosclerotic disease. Our study shows that pre-operative factors believed to increase the risk of death and stroke in diabetics include higher low-density lipoprotein values, coronary artery disease and peripheral arterial disease. A prompt diagnosis of these co-morbidities and the use of statins should reduce mortality and stroke rates after CEA. Dorigo and co-workers state that patients with diabetes were predominantly women, who suffered from coronary artery disease, peripheral arterial disease and hyperlipidaemia.6 Other authors claim that pre-CEA diagnosed risk factors such as atherosclerosis and diabetes had an effect on 30-day mortality rate and stroke, but they did not record a significant influence from dyslipidaemia.17 Our research, however, has identified most frequent postoperative complications, such as post-operative MI, coronary insufficiency, TIA, CVI, respiratory insufficiency, post-operative bleeding and wound infection. All these complications were significantly more prevalent in patients with DM. Post-operative TIA was present in 0.9% of patients without DM and in 3.6% of patients with DM (p = 0.009), while postoperative CVI was 1.3 versus 3.2%, respectively (p = 0.072). Patients with DM suffer significantly more often from early post-operative TIA and CVI. The greater risk of cerebrovascular infarction in patients with DM was reported in the recent review by Hussain et al., wherein they determined that DM was associated with a 1.5-times greater risk of stroke after CEA.18 Contrary to these statements, Ballota et al. suggest that there is no important difference in the frequency of these post-operative complications between diabetics and non-diabetics.10 Post-operative cardiological complications, including MI, occurred in 1.1% of patients without DM and in 3.6% of patients with DM (p = 0.039). However, that can be explained by the fact that our study pool consisted of a group of diabetics whose pre-operative cardiological complications were generally more prevalent. Altinbas and co-workers suggest no significant difference in post-operative cardiac events, and noted that after CEA a consequent coronary insufficiency occurred in 2.3% of cases, with no difference observed between the groups concerned.19 Ombrellaro et al. recently observed in postCEA patients undesirable cardiac events such as MI and CHF in 14.3% of patients with diabetes and in 16% of the non-diabetic group. The difference was not statistically significant.20 The frequency of haematoma of the operated wound occurred in 2.4% of non-DM patients and in 3.6% of DM patients, while wound infection was present in only patients with DM (1.8%). Zhao et al. stated that the incidence of haematoma was relatively high in diabetics, the cause being pre-operative high doses of heparin (1 mg/kg), as well as double antiaggregation therapy.17 The same authors specify that diabetes may increase the possibility of wound and systemic infection, and that preoperative HbA1c levels should be about 7% to reduce possible infections.17 Post-operatively, 50% carotid restenosis in the course of one year was not significant; it occurred in 2.2% of non-DM patients and in 1.8% of DM patients (χ2 = 0.124; p = 0.724). Other investigations produced similar results.19 Total post-operative mortality (neurological and cardiological) was present in 0.9% of non-diabetics and in 2.5% of diabetics (p = 0.113). Ahari et al. report in their study that diabetics had higher 30-day mortality rates (3.2 vs 1.4%; p = 0.02).5 Total post-operative complications were observed in 8.5% of non-diabetics and in 18.3% of DM patients (p < 0.001). DM patients were at more than two times greater risk of suffering from post-operative complications. Dorigo et al. found that the risk of post-operative complications was twice as high in patients suffering from DM.6 The study by Jeong et al. concluded that DM patients were not at a greater risk of 30-day morbidity and mortality after CEA than those without DM.16 Our patients on oral antidiabetics suffered considerably more often from post-operative complications than those on insulin (25.4 vs 8.2%; p < 0.001). In the study by Axelrod et al. there was a somewhat higher percentage of post-operative complications in the diabetics, although without a significant difference between the patients on insulin and those on oral antidiabetics.21 Dimic et al. have shown the cumulative rate of TIA/cerebrovascular infarction (p = 0.02) to be greater in insulin-dependent diabetics (IDDM) than in those who are insulin-independent (IIDM).22 Similarly, Bennett et al. stated that insulin-necessitated DM is one of the independent predictors of high morbidity and mortality rates among the patients who have undergone CEA.23 However, Dorigo and co-workers discovered that patients with diabetes were at greater risk of death, but with no difference between the patients with insulin-controlled diabetes and those on oral medication.6 Parlani and colleagues reported that patients with IDDM had higher rates of cerebrovascular infarction and death (6.5 vs 1.7%; p = 0.02) than non-diabetics.7 CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing information, refer to the professional information approved by SAHPRA, 13 December 2019. 1) Panagiotis C Stafylas, Pantelis A Sarafidis. Carvedilol in hypertension treatment. Vascular Health and Risk Management 2008;4(1):23-30. CDA891/09/2022. www.pharmadynamics.co.za CUSTOMER CARE LINE +27 21 707 7000 RESTORE cardiac function ß C A R V E D I L O L 6,25 mg 12,5 mg 25 mg CARVEDILOL: • is indicated twice daily for mild to moderate stable symptomatic congestive heart failure • is indicated once daily for essential mild to moderate hypertension • has no significant metabolic eects1
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 28 VOLUME 19 NUMBER 2 • November 2022 Comparably, Pothof et al. stated that patients with IDDM had higher rates of 30-day cerebrovascular infarction and death than those without diabetes (3.4 vs 1.5%; p < 0.001).24 In our series, a more significant rate of mortality and postoperative complications occurred in diabetics being treated with oral antidiabetics, compared to those being treated with insulin, which conflicts other studies that reported a higher frequency of complications in groups on insulin therapy. To some extent, this can be explained by extremely lengthy and irregular therapy of patients on oral antidiabetic agents, which leads to chronic, atherosclerotic changes in the blood vessels. Patients on insulin may be more diligent in their therapy. With regard to long-term regulation of glycaemia, our patients with post-operative complications had significantly higher values of HbA1c (t = 5.010; p < 0.001). Tanashian et al. reported that the presence of DM was associated with an increased risk of ischaemic lesions in the brain and a higher percentage of post-operative complications, associated with increased values of glycaemia (8.0 mmol/l) and HbA1c (7.8–8%) in the pre-operative phase. 25 Dimic et al. stated that the group of diabetics with HbA1c > 7% had a greater cumulative rate of TIA/cerebrovascular infarctions (p = 0.03).22 Parr et al. reported that patients with IDDM, when compared to those with IIDM, had higher rates of cerebrovascular infarction (3.27, 0.93 and 0.94%; p < 0.0001), MI (3.35, 1.10 and 0.87%, p < 0.0001) and hospital mortality (p < 0.0001).26 Jeong et al. have shown that insulin use was associated with a higher rate of mortality and morbidity. The absence of data on serial measurements of HbA1c levels in their analysis was the reason they could not explain differences in glycaemic control.16 It is certain that high concentrations of low-density lipoprotein and chronic hyperglycaemia, indicated by high HbA1c levels, increases the development of atherosclerosis, which sets in earlier and is more pervasive in diabetics. On the basis of the results of our investigation, it is believed that the percentage of post-operative complications may be reduced by means of a better regulation of glycaemia, lower values of HbA1c, prompt diagnosis of glucose intolerance and regular and adequate antidiabetic therapy. Considering the small number of studies that have dealt with this kind of investigation of complications related to diabetes therapy, the hypothesis remains to be proven in similar future randomised studies. Conclusions In comparison to other studies, this research, possibly for the first time, included a large number of patients for a short time period, a high percentage of diabetics were included, the investigation was conducted in diabetics on different types of antidiabetic therapy, and the occurrence of complications was determined according to values of glycosylated haemoglobin. The results of this study indicate that diabetes was an independent risk factor for fatal and non-fatal cardiac or neurological events after CEA since it caused 2.5 times more post-operative complications in the group of diabetic patients. Our study also recorded a higher rate of mortality and post-operative complications, as well as higher HbA1c values in the diabetics on oral antidiabetics than in those on insulin therapy. This was in conflict with similar studies. Ultimately, these results show that CEA was a reliable and efficient method of surgical treatment of the patients with significant carotid stenosis and concomitant diabetes mellitus, regardless of the type of antidiabetic therapy. References 1. Radak D, Tanaskovic S, Ilijevski N, et al. Eversion carotid endarterectomy versus best medical treatment in symptomatic patients with near total internal carotid occlusion: a prospective nonrandomized trial. Ann Vasc Surg 2009; 24: 185–189. 2. Noh M, Kwon H, Jung CH, et al. Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study. Cardiovasc Diabetol 2017; 16: 74. 3. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991; 337: 1235–1243. 4. Hegele RA, Eliasziw M, De Angelis M. Sex, diabetes, and stroke after carotid endarterectomy. Diabetes Care 2003; 26: 1641. 5. Ahari A, Bergqvist D, Troeng T, et al. Diabetes mellitus as a risk factor for early outcome after carotid endarterectomy – a population-based study. Eur J Vasc Endovasc Surg 1999; 18: 122–126. 6. Dorigo W, Pulli R, Pratesi G, et al. Early and long-term results of carotid endarterectomy in diabetic patients. J Vasc Surg 2011; 53: 44–52. 7. Parlani G, De Rango P, Cieri E, et al. Diabetes is not a predictor of outcome for carotid revascularization with stenting as it may be for carotid endarterectomy. J Vasc Surg 2012; 55: 79–89. 8. Adegbala O, Martin KD, Otuada D, et al. Diabetes mellitus with chronic complications in relation to carotid endarterectomy and carotid artery stenting outcomes. J Stroke Cerebrovasc Dis 2017; 26: 217–224. 9. Rockman CB, Saltzberg SS, Maldonado TS, et al. The safety of carotid endarterectomy in diabetic patients: clinical predictors of adverse outcome. J Vasc Surg 2005; 42: 878–883. 10. Ballotta E, Da Giau G, Renon L. Is diabetes mellitus a risk factor for carotid endarterectomy? A prospective study. Surgery 2001; 129: 146–152. 11. Mizuhashi S , Kataoka H, Sano N, et al. Impact of diabetes mellitus on characteristics of carotid plaques and outcomes after carotid endarterectomy. Acta Neurochir (Wien) 2014; 156: 927–933. 12. Danaei G, Lawes CM, Vander Hoorn S, et al. Global and regional mortality from ischaemic heart disease and stroke attributable to higherthan- optimum blood glucose concentration: comparative risk assessment. Lancet 2006; 368: 1651–1659. 13. AbuRahma AF, Robinson PA, Strickler DL, et al. Proposed new duplex classification for threshold stenoses used in various symptomatic and asymptomatic endarterectomy trials. Ann Vasc Surg 1998; 12: 349–358. 14. Huybrechts KF, Caro JJ, Xenakis JJ, et al. The prognostic value of the modified Rankin scale score for long-term survival after first-ever stroke. Results from the Athens Stroke Registry. Cerebrovasc Dis 2008; 26: 381–387. 15. Halliday AW, Thomas D, Mansfield A. Steering Committee. The Asymptomatic Carotid Surgery Trial (ACST). Rationale and design. Eur J Vasc Surg 1994; 8: 703–710. 16. Jeong M-J, Kwon H, Jung CH, et al. Comparison of outcomes after carotid endarterectomy between type 2 diabetic and non-diabetic patients with significant carotid stenosis. Cardiovasc Diabetol 2019; 18: 41. 17. Zhao K, Wu W, Zhao J, et al. [Effectiveness analysis of carotid endarterectomy in diabetic patients suffering from carotid stenosis]. Zhonghua Yi Xue Za Zhi 2015; 95(44): 3584–3587. 18. Hussain MA, Bin-Ayeed SA, Saeed OQ, et al. Impact of diabetes on carotid artery revascularization. J Vasc Surg 2016; 63: 1099–1107. 19. Altinbas A, Algra A, Brown MM, et al. Effects of carotid endarterectomy or stenting on hemodynamic complications in the International Carotid Stenting Study: a randomized comparison. Int J Stroke 2014; 9: 284–290. 20. Ombrellaro MP, Dieter RA, Freeman M, et al. Role of dipyridamole myocardial scintigraphy in carotid artery surgery. J Am Coll Surg 1995; 181: 451–458 21. Axelrod DA, Upchurch GR Jr, DeMonner S, et al. Perioperative cardiovascular risk stratification of patients with diabetes who undergo elective major vascular surgery. J Vasc Surg 2002; 35: 894–901. 22. Dimic A, Markovic M, Vasic D, et al. Impact of diabetes mellitus on early outcome of carotid endarterectomy. Vasa 2019; 48: 148–156. 23. Bennett KM, Scarborough JE, Shortell CK. Predictors of 30-day postoperative stroke or death after carotid endarterectomy using the 2012 carotid endarterectomy-targeted American College of Surgeons National Surgical Quality Improvement Program database. J Vasc Surg 2015; 61: 103–111. 24. Pothof AB, O’Donnell TFX, Swerdlow NJ, et al. Risk of insulindependent diabetes mellitus in patients undergoing carotid endarterectomy. J Vasc Surg 2019; 69: 814–823. 25. Tanashian MM, Skrylev SI, Antonova KV, et al. Carotid revascularization in type 2 diabetes mellitus. Significance of chronic hyperglycaemia. Angiol Vasc Surg 2017; 23: 99–106. 26. Parr MS, Dombrovskiy VY, Nagarsheth KH, et al. Diabetes control decreases morbidity and mortality after carotid endarterectomy. Surgery 2018; 163: 404–408.
VOLUME 19 NUMBER 2 • November 2022 29 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW The use of fenugreek in ameliorating hyperglycaemia and diabetes Correspondence to: Dr Chandralekha Mohan Department of Family Medicine, University of KwaZulu-Natal, Durban e-mail: docmohan7@gmail.com S Afr J Diabetes Vasc Dis 2022; 19: 29–32 Introduction Fenugreek is Trigonella foenum graecum. Trigonella is a Greek word meaning ‘little triangle’, due to its yellowish-white triangular flowers. Fenugreek is one of the oldest medicinal plants from the Fabaceae family. Its origins can be traced back to 4000 BC in Central Asia.1 Its description and benefits have been reported in the Ebers Papyrus, one of the most ancient medicinal documents in 1500 BC in Egypt.2 Fenugreek is commercially grown in India, Nepal, Afghanistan, Iran, Egypt, France, Morocco, Spain, China, Turkey, North Africa, Italy, Pakistan, Ukraine and Argentina.3 It grows well under a wide range of conditions, and is moderately tolerant of drought and high salinity. The nutritional constituents of fenugreek include fibre, phospholipids, glycolipids, oleic acid, linolenic acid, linoleic acid, CHANDRALEKHA MOHAN Abstract Diabetes mellitus is one of the most debilitating noncommunicable diseases of the century. It has an increasing prevalence worldwide. It is predicted that by 2040, more than half a billion people globally will suffer from diabetes. One of the main ways to prevent diabetes is to eat healthily. It is well known that patients with chronic diseases add supplements to their treatment regimens. During the last four decades, cellular and animal studies have reported convincing evidence to show that fenugreek has hypoglycaemic and lipid-lowering properties in prediabetics, and in insulin-dependent and non-insulindependent diabetics. Fenugreek has a protective effect against diabetic complications through immunomodulation, stimulation of insulin secretion and antioxidant properties, inhibition of inflammation in adipose tissues, enhancing adipocyte differentiation, and by preventing pancreatic and renal damage. There are four bio-active components that are present in fenugreek, which are beneficial in ameliorating the effects of hyperglycaemia and diabetes. They are an amino acid, 4-hydroxyisoleucine, diosgenin, saponins, and the fibre in fenugreek. This article reviews the scientific evidence relative to the use of fenugreek in ameliorating hyperglycaemia and diabetes. choline, vitamins A, B1, B2, C, nicotinic acid and niacin.4 The seeds, leaves, powder extracts and oils of the fenugreek plant are used extensively throughout the world as foods, in spices, and as traditional medicine5,6 (Table 1, Fig. 1). Fenugreek is known by different names in the world: methi in India, dari in Iran, hulba in Arabia, heyseed in England, moshoseitaro in Greece, hu lu ba in China and shoot in Israel. Table 1. Therapeutic and other uses of fenagreek Other uses Therapeutic benefits Food Non-food anticarcinogenic bread making cosmetics antiviral vegetable dyes antimicrobial food gum insect repellent anticholesterolaemic flavouring agent paints antihypertensive forage perfumes antioxidant alcoholic beverages fumigant galactogogue syrups emmolient laxative androgenic and anabolic effect in males Fig. 1. Fenugreek seeds, plant and powder. The role of fenugreek in diabetes and dyslipidaemia Various animal and human studies over the last four decades have shown that treatment with fenugreek was associated with lessening of the glucose tolerance curve, improvement in the glucoseinduced insulin response, and reduction in insulin resistance7 (Table 2). These effects were mainly due to 4-hydroxyisoleucine, isolated from fenugreek seeds (Fig. 2).
30 VOLUME 19 NUMBER 2 • November 2022 REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE Table 2. Chronological research studies of fenugreek on animals and humans Year Human/animal Effects References 1970–1980 Rats and dogs Hypoglycaemia 8, 9, 10, 11 1988 Humans Decrease in postprandial glucose levels 12 1990 Humans Lowering of fasting blood sugar, reduction in total cholesterol, 13 LDL-C, VLDL-C, and triglycerides in type 1 diabetes 1995 Rats Dose-related hypoglycaemic effect in normal and diabetic rats 14 1998 Rats and humans 4-hydroxyisoluecine augments glucose-induced insulin from 15 islets of Langerhans 1998 Rats Antidiabetic effect of 4-hydroxyisoleucine 16 2001 Rats Fenugreek normalised antioxidant status 17 2001 Humans Improved glycaemic control, reduced insulin resistance 18 and favourable effect on triglycerides 2002 Rabbits Hypoglycaemic effect due to improvement in glucose- 19 induced insulin response 2004 Rats Reversal of diabetic state at a cellular level. Metabolic normalisation 20 resulting in protective effect on liver and kidney 2007 Rats Reduced blood glucose and lipids 21 2007 Humans Blood glucose levels reduced 22 2009 Humans Fasting glucose, triglycerides, VLDL-C decreased 23 2009 Rats Hypoglycaemic effect with fenugreek extract 24 2010 Rats Fenugreek oil improved blood glucose levels 25 2010 Mice Diosgenin enhanced adipocyte differentiation and inhibited 26 inflammation in adipose tissue 2014 Humans Meta-analysis showed fenugreek seeds had 27 beneficial glycaemic control in diabetic patients 2014 Rats Improved insulin resistance by promoting mitochondrial biogenesis 28 2015 Humans Decreased levels of fasting blood sugar, postprandial glucose 29 and lipids, decreased insulin resistance. No adverse effects. 2016 Humans Fenugreek saponins 500 mg bd decreased fasting blood sugar levels. 30 No adverse effects. Decreased postprandial glucose levels 2019 Humans Fenugreek seed powder solution improved lipid metabolism in type 2 31 diabetics. No adverse effects 2020 Humans 5 g fenugreek seed powder tds improved fasting blood sugar levels in 32 diabetic patients taking antidiabetic drugs compared to controls (p = 0.024) LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol. Contra-indications and side effects Fenugreek supplements should not be taken by women with breast cancer. It should not be taken by persons on anticoagulants such as wafarin. Breast-feeding women taking fenugreek as a galactagogue should be cautious if suffering from asthma or cardiovascular disease. The main side effects of fenugreek are gastrointestinal. Fenugreek usage in studies showed no hepatic or renal toxicity.33 Conclusion Food is undoubtedly a major determinant of human health that is under one’s control. Food constituents that have antioxidants, vitamins, fibre and protein can prevent ageing and the onset of chronic metabolic disorders, cancers and heart disease. By virtue of its use as a medicinal herb for many centuries and its relative Fig. 2. 4-hydroxyisoleucine molecule.
VOLUME 19 NUMBER 2 • November 2022 31 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW safety,34,35 fenugreek shows much promise as a cost-effective herbal drug and adjuvant to manage diabetes. However more robust, long-term studies with better methodology and study design are required. References 1. Altunas E, Ozgoz, Taser OF. Some physical properties of fenugreek (Trigonella foenum graecum L) seeds. J Food Eng 2005; 71: 37–43. 2. Betty R. Spice India. The Many Healing Virtues of Fenugreek. 2008: 17–19. 3. Bahmani M, Shirzad H, Mirhosseini M, Mesripour A, Rafieian-Kopaei M. A review on ethnobotanical and therapeutic uses of fenugreek. J Evidence-Based Complement Altern Med 2016; 21(1): 53–62 4. Ahmad A, Alghamdi SS, Mahmood K, Afzal M. Fenugreek, a multipurpose crop: Potentialities and improvements. Saudi J Bio Sci 2016; 23(2): 300–310. 5. Nagulapalli VKC, SwaroopA, Bagchi D, Bishayee A. A small plant with big benefits. Fenugreek (Trigonella foecun graecum Linn.) for disease prevention and health promotion. Molec Nutr Food Res 2017; 61(6). 6. Haber SL, Keonavong J. Title? Am J Health-System Pharm 2013; 70(14): 119– 120. 7. Mosawi AJ. The use of fenugreek supplementation in diabetes. Endocrinol Disord 2021; 5(5). 8. Mishkinsy JS, Goldschmied A, Joseph B, Abronson Z, Sulman FG. Hypoglycaemic effect of Trigonella foecum graecum and Lupinus termis (Leguminosae) seeds and their major alkaloids in allocan-diabetic and normal rats. Arch Int Pharmacodyn Ther 1974; 210(1): 27–37 9. Ghafghazi T, Sheriat HS, Dastmalchi T, Barett RC. Antangonism of cadmium and allocan-induced hyperglycaemia in rats by Trigonella foenum graecum. Pahlavi Med J 1971; 8(1): 14–25. 10. Ribes G, Sauvaire Y, Baccou JC, Valette G, Chenon D, Trible ER, LoubatieresMariani MM. Effects of fenugreek seeds on endocrine pancreatic secretions in dogs. Ann Nutr Metab 1984; 28(1): 37–43. 11. Ribes G, Sauvaire Y, Da Costa C, Baccou JC, Loubartieres-Mariani MM. Antidiabetic effects of subfractions from fenugreek seeds in diabetic dogs. Proc Soc Exp Biol Med 1986; 182(2): 159–166. 12. Madar Z, Abel R, Samish S, Arad J. Glucose-lowering effects of fenugreek in noninsulin-dependent diabetics. Euro J Cli Nutr 1988; 42(1): 51–54. 13. Sharma RD, Raguram TC, Rao NS. Effects of fenugreek seeds on blood glucose and serum lipids in type 1 diabetics. Euro J Clin Nutr 1990; 44(4): 301–306. 14. Khosla P, Gupta DD, Nagpal RK. Effect of Trigonella foenum graecum (fenugreek) on blood glucose in diabetic rats. Indian J Physiol Pharmacol 1995; 39(2): 173– 174. 15. Sauvaire Y, Petit P, Broca C, Manteghetti M, Baissac Y, et al. 4-Hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. Diabetes 1998; 47: 206–210. 16. Broca C, Gross R, Petit P, Sauvaire Y, Manteghetti M, et al. 4-Hydroxyisoleucine: experimental evidence of its insulinotropic and antidiabetic properties. Am J Physiol 1998; 277: E617–E623 17. Anuradha CV, Ravikumar P. Restoration of tissue antoxidants by fenugreek seeds (Trigonella foenum graecum) in alloxican diabetic rats. Indian Physiol Pharmacol 2001; 45: 408–420. 18. Gupta A, Gupta R, Lal B. Effect of Trigonella foenum graecum (fenugreek) seeds on glycaemic control and insulin resistance in type 2 diabetes mellitus: a doubleblind placebo-controlled study. J Assoc Physicians India 2001; 49: 1057–1061. 19. Puri D, Prabhu KM, Murthi PS. Mechanism of action of a hypoglycaemic principle isolated from fenugreek seeds. Indian J Physiol Pharmacol 2002; 46: 457–462. 20. Thakran S, Siddiqui MR, Baquer NZ. Trigonella foenum graecum seed powder protects against histopathological abnormalities in tissues of diabetic rats. Mol Cell Biochem 2004; 266: 151–159. 21. Xue WL, Li XS, Zhang J, et al. Effect of Trigonella foenum – graecum (fenugreek) extract on blood glucose, blood lipids and hemorheological properties in streptozotocin-induced diabetic rats. Asia Pac J Clin Nutr 2007; 16: 422–426. 22. Lu FR, Shen L, Quin Y, et al. Clinical observation on Trigonella foecum graecum L total saponins in combination with sulphonylureas. I: the treatment of type 2 diabetes mellitus. Chin J Integr Med 2008; 14: 56–60. 23. Kassaian N, Azadbakht L, Forghani B Amini M. Effect of fenugreek seeds on blood glucose and lipid profiles in type2 diabetic patients. Int J Vitamin Nutr Res 2009; 79: 34–39. 24. Mowla A, Alauddin M, Rahman MA, Ahmed K. Antihyperglycaemic effect of Trigonella foenum graecum (fenugreek) seed extract in alloxan-induced diabetic rats and its use in diabetes mellitus: A brief qualitative phytochemical and acute toxicity test on the extract. Afr J Tradit Complement Altern Med 2009; 6: 255– 261. 25. Hamden K, Masmoudi H, Carreau S, et al. Immunomodulatory, beta-cell, and neuroprotective actions of fenugreek oil from alloxan-induced diabetes. Immunopharmacol Immunotoxicol 2010; 32(3): 437–445. 26. Uemura T, Hiral S, Misoguchi N, Goto T, Lee JY, et al. Diosgenin present in fenugreek improves glucose metabolism by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues. Mol Nutr Food Res 2010; 54: 1596–1608. 27. Neelakantan N, Naayayanan M, de Souza RJ, van Dam RM. Effect of fenugreek (Trigonella foenum graecum L.) intake on glycaemia: a meta-analysis of clinical trials. Nutr J 2014; 13: 7. 28. Rawat AK, Korthikunta K, Gautam S, et al. 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis. Fitoterapia 2014; 99: 307– 317. 29. Gaddam A, Galla C, Thumisetti S, et al. Role of fenugreek in prevention of type 2 diabetes mellitus in prediabetes. Metab Disord 2015; 14: 74. 30. Verma N, Usman K, Patel N, et al. A multicenter clinical study to determine the efficacy of a novel fenugreek seed (Trigonella foenum graecum) extract (Fenfuro) in patients with type 2 diabetes. Food Nutr Res 2016; 60: 32382. 31. Geberemeskel GA, Debebe YG, Nguse NA. Antidiabetic effect of fenugreek seed powder solution (Trigonella foecum – greacum L) on hyperlipidaemia in diabetic patients. J Diabetes Res 2019: 8507453. 32. Hadi A, Arab A, Hajianfar H, et al. The effect of fenugreek seed supplementation on serum insulin levels, blood pressure, liver and kidney function in patients with diabetes mellitus. A parallel randomized clinical trial. Complement Ther Med 2020; 49: 102315. 33. Gong J, Fang K, Dong H, et al. Effect of fenugreek on hyperglycaemia and hyperlipidaemia in diabetes and prediabetes: A meta-analysis. J Ethnopharmacol 2016; 194: 260–268. 34. Flammang AM, Cifone MA, Erexson GL, Stankowski LF. Genotoxity testing of a fenugreek extract. Food Chem Toxicol 2004; 11: 1769–1775. 35. Kandhare AD, Thakurdesai PA, Wangikar P, Bodhankar SL. A systematic literature review of fenugreek seed toxicity by using ToxRTool: evidence from preclinical and clinical studies. Heliyon 2019; 5(4): 1536. IVOLAN 5 mg. Each tablet contains Ivabradine oxalate equivalent to 5 mg Ivabradine base. S3 51/7.1.4/0921. For full prescribing information, refer to the professional information approved by SAHPRA, March 2021. IVNB836/05/2022. IMPROVE QUALITY OF LIFE www.pharmadynamics.co.za CUSTOMER CARE LINE +27 21 707 7000
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