The Ability of Combination Sulfonylurea and Metformin in Reducing Morbidity and Mortality in Type 2 Diabetes

Introduction

The World Health Organisation (WHO) (2022) estimated that between 1980 to 2014, the prevalence of diabetes increased from 108 million to 422 million worldwide. Diabetes takes many different forms, such as type 1, type 2, gestational, type 3, Maturity Onset Diabetes of the Young (MODY), and Latent Autoimmune Diabetes in Adults (LADA) (Diabetes UK, 2019). Type 2 diabetes accounts for around 85% of the diabetic population, making it the most prevalent type [1]. During normal physiological conditions, blood glucose level is maintained and regulated by the islets of Langerhans located in the pancreas; insulin is secreted in response to elevated glycaemic levels and facilitates the transfer of glucose into muscle and fat cells for energy utilisation [1].

Under abnormal conditions in type 2 diabetes, however, the pancreas fails to produce sufficient insulin, or the insulin produced is deficient. This progressive autoimmune disease is linked to genetic causes, obesity and/or poor diet [2]. Metformin, a common treatment for type 2 diabetes, is part of the biguanide class of medicines and functions in reducing hepatic glucose output by suppressing gluconeogenesis. In contrast, sulfonylureas act by stimulating the pancreatic beta cells to increase the amount of insulin released and efficiency [3]. Here, the authors examined if combinatorial Sulfonylurea and Metformin therapy had the ability to reduce morbidity and mortality in Type 2 Diabetes. 

Methodology

A comprehensive search of the databases NU Search, PubMed, Ovid, Embase, CINAHL and Medline was undertaken to identify studies for inclusion. The inclusion criteria were patients with type 2 diabetes, aged >18, taking metformin and/or sulfonylureas, assessing the safety and efficacy of combination therapy. The exclusion criteria were participants with other types of diabetes, patients aged <18, and patients taking insulin or other subcutaneous injection anti-diabetes medications. The following key search terms were entered into the selected online databases: type 2 diabetes + oral + metformin + sulfonylurea + adults + morbidity + mortality.

The search returned a total of 1057 studies. After reviewing each study manually, and assessing against inclusion and exclusion criteria, 1045 studies were excluded. A total of 11 studies met the inclusion criteria and were included in this review. A Critical Appraisal Skills Programme (CASP, 2020) was utilised for data extraction and assess the risk of bias. Each study was read, synthesized and the main outcomes described.

Results and Discussion

Theme one - Cardiovascular risk

Cardiovascular risk and diabetes have a well-documented association, and Diabetes UK (2019) states that the risk is increased by 2 and a half times for stroke or heart attack, which highlights the importance of reducing the risk. Ten of the eleven studies by Gillani et al. (2022), Wang, Wua, and Chiena, (2021), Douros et al. (2018), Chang et al. (2015), Leiter et al. (2015), Nauck et al. (2014), Del Prato et al. (2014), Hassan and Abd-Allah (2015), Pantalone et al. (2012), and Nauck et al. (2011) reported cardiovascular risk/mortality for 166,767 participants [4 -13]

Dpp4i Versus Sulfonylurea and Metformin

Of the ten studies, two of the studies by Gillani et al. (2022) and Wang et al. (2021) revealed that combination metformin and DPP4i versus SU and metformin, concurred that DPP4i combination had better cardioprotective effects [4,5]. Assessed Atherosclerotic Cardiovascular Disease (ASCVD) risk and identified a significant mean reduction -1.1 % from baseline for sulfonylureas plus metformin combined, and DPP4i and metformin – 1.56%. SU and DPP4i were both found to reduce ASCVD risk score, however DPP4i’s were superior. The study also found gliclazide exhibited an enhanced cardiovascular profile to glimepiride. The results of Wang et al. (2021) found that DPP4i combination was superior, with better protective effects than SU combined for, Heart failure (HF) HR 0.86 DPP4i versus 1.0 SU, Cerebrovascular disease HR 0.72 versus 1.0 Myocardial Infarction (MI), DPP4i= 340, HR 1.0, versus SU =402, HR 0.84 [5].

Metformin and Sulfonylurea Combinations

Of the ten studies, two by Hassan and Abd-Allah (2015) and Pantalone et al [11,12]. Assessed different combinations of SU and metformin. Assessed lipid profiles, and found Low density lipoprotein (LDL) improved from baseline, but suggested greater reduction of cardiovascular risk with glimepiride and metformin 142+7, versus gliclazide and metformin 146+7. Pantalone et al. (2012) found no significant difference in mortality across groups with metformin plus, glimepiride, versus metformin and glipizide HR 1.03, or metformin plus glimepiride HR 1.03 or glipizide and metformin versus metformin plus glibenclamide, HR 1.05. there were 636 deaths in the cohort [12].

Sulfonylurea and Metformin Versus SGLT2i

Leiter et al. (2015) assessed high density lipoprotein (HDL) and was found to be reduced in patients that received metformin and sulfonylurea combination 0.06 versus SGLT2i 0.38, however this was not statistically significant. Nauck et al. (2011), also reported results concomitant with Leiter et al. (2015) that HDL was increased in the SGLT2i group and reduced in the SU group. The 156-week extension study Nauck et al. (2014) did not report outcomes HDL. The extension study by Nauck et al. (2014) reported the additional cardiac outcomes, coronary artery occlusion (CAO) and aortic aneurysm (AA) but no differences were identified across groups [8,13]

Sulfonylurea and Metformin Vs Glinides and A- Glucosidase

Chang et al. (2015) identified that the metformin and glinides, N=9 or alpha glucosidase inhibitor N=13, Versus N=323 in SU and metformin group. significantly reduced the risk of MI, but showed no variance in risk of stroke or HF.

Sulfonylureas and Metformin Versus Sglt2i, Dpp4i And Su Combinations

Six of the ten studies by Douros (2018), Chang et al. (2015), Del Prato et al. (2014), Nauck et al. (2014), Pantalone et al. (2012) and Nauck et al. (2011) found no substantial difference between the study groups for cardiovascular risk of different events, including cardiovascular death, MI, CVD, stroke and heart failure, between combination SU with metformin, versus SGLT2i, DPP4i, and SU combinations. Though it would be important to note Nauck et al. (2011) suggested that persistent reduction in systolic blood pressure and weight with SGLT2i may exert a favourable effect on cardiovascular risk, but not a significant finding [6,7,9, 10,12,13].

After reviewing the results from all ten studies assessing cardiovascular risk and mortality, the studies confirm that combination metformin and sulfonylurea reduced cardiovascular risk to a degree, and some SU’s might be associated with a further reduced risk than others. However, the evidence is not strong enough to form a sound conclusion on the different types of SU. When comparing the performance of metformin and sulfonylureas to other anti-diabetic medicines, the results were inconclusive. Six out of ten, did not show a meaningful reduction of cardiovascular risk. More robust research is needed to further investigate this points out that SGLT2i combination with metformin may provide beneficial cardioprotective effects, which is supported by the current guidance by the National Institute for health and Care Excellence (2015) which advocates the use of SGLT2i for patients with cardiovascular risk or existing cardiac disease, rather than SU which is in keeping with the findings from the studies included in this review [4,5,11]. conducted their studies in settings that were vastly different, Malaysia, Egypt and Taiwan which limits the generalisations that can be made from this research. Two of the studies by Gillani et al. (2022) and Wang et.al. (2021) indicated enhanced cardioprotective effects of DPP4i in comparison to SU, however both had risk of bias. Gillani et al. (2022) may have introduced selection bias, as participants self-referred or were recommended by study sites [2,5]. Wang et al. (2021) had a large sample size which increases the validity. However, the retrospective cohort study design, reduces the strength of the results [5]. Additionally, the information was taken from an insurance database where there was potential for data to be missing. In the initial study by Nauck et al. (2011) HDL was reported as increased with the SGLT2i group and reduced in the SU groups [13]. The extension study Nauck et al. (2014), did not report outcomes for HDL, this could indicate reporting bias [14].

Theme Two - HbA1c Reduction

The second theme emerging from the results was HbA1C levels. Chen et al. (2015) explained that macrovascular complications in diabetes are associated with poor control of HbA1c and is linked to the pathophysiology of vascular damage.

Eight of the eleven studies by Gillani et al. (2022), Muskiet et al. (2020), Hollander et al. (2017) Hassan and Abd-Allah (2015), Leiter et al. (2015), Del Prato et al. (2014), Nauck et al. (2014) Nauck et al. (2011) assessed outcome for HbA1c levels in 8925 participants.

Sulfonylurea and Metformin Versus Dpp4i and Metformin

Two of the eight studies by Gillani et al. (2022) and Del Prato et al. (2014) found whilst HbA1c was improved with SU’s and metformin 7.93 +1.69, there was a greater improvement with DPP4i 7.86 + 1.92 at end point [2,10]. Gillani et al. (2022) and Del Prato et al. (2014) found that HBA1c was reduced with SU’s but noted a greater reduction with DPP4i and metformin over 24 and 104 weeks. 6.73 -2.65 metformin and SU, versus 6.22- 2.07 with metformin and DPP4i, a 0.72% mean change for DDP4i, versus 0.59%, for metformin and SU respectively.

One of the eight studies by Muskiet et al. (2020) found similar reductions for DPP4i linagliptin and SU glimepiride across both groups - 0.10% and -0.09% respectively from baseline to endpoint assessment after 8 weeks.

Sulfonylurea and Metformin Versus Sglt2i and Metformin

Four of the Eight studies Hollander et al. (2017), Leiter et al. (2015) Nauck et al and Nauck et al. (2011), assessed SGLT2i’s. Two of which, by Hollander et al. (2017) and Leiter et al. (2015) concurred that there was a sharp fall in HbA1c with SU at 6 -18 weeks. Both SGLT2i’s, ertugliflozin and canagliflozin, demonstrated an advantage in results over SU’s. Hollander et al. (2017) showed a reduction of -1.2 for ertugliflozin and metformin, versus -0.7 glimepiride and metformin. The results for Leiter et al. (2015) showed a reduction of -1.39 SGLT2i and metformin, versus metformin and SU -0.55. Both trials established non-inferiority between SGLT2i and SU [14,8].

Nauck et al. (2011) and Nauck et al. (2014) assessed SU versus SGLT2i, and found that glipizide had an earlier reduction in HbA1c in from baseline to week 18. At week 52, Nauck et al. (2011) found no difference between the groups. SU -0.52%, and SGLT2i -0.52%. However, at 104 weeks dapagliflozin showed a greater and sustained reduction in HbA1c, with a reduction of -0.32 for metformin and SGLT2i, and -0.14 for SU and metformin [13,9].

Different Combinations of Sulfonylurea with Metformin

Hassan and Abd-Allah (2015) compared different combinations of SU with metformin and found that glimepiride performed superior to gliclazide at 3months in reducing HbA1c. The results were Glimepiride and metformin 7±0.1, compared to 7.1±0 for Gliclazide and metformin [11].

The results here indicated a consensus towards sulfonylureas being effective in reducing HbA1c. All eight recorded a significant reduction from baseline.

A combined loss of -1.59 for SU and metformin, versus DPP4i and metformin -2.43 versus -2.91 for SGLT2i and metformin. However, four of the eight studies and the extension study by Nauck et al. (2011) found that HbA1c had a more rapid reduction in the early stages of the studies with SU and metformin. However, SGLT2i’s had a longer sustained lowering than SU at endpoint. Chen and Li (2019) also supported this finding in their systematic review, as SGLT2i’s were shown to be more effective over longer periods of time than SU’s and have similar effects in the short term [8,9,13-15].

Similar to SGLT2i, DPP4i also demonstrated better efficacy long term in comparison to SU. A review conducted by Deacon and Lebovitz (2016), also supports this finding. Current guidance from National Institute for Health and Care Excellence (NICE) (2022) recommends the use of SU’s as rescue therapy, and advise to review the treatment, once glucose levels are under control. This correlates with its ability to rapidly reduce HbA1c in the studies above. The evidence confirms the efficacy of sulfonylurea in reducing HbA1c but suggest DPP4i and SGLT2i are an effective alternative treatment to SU [16]. Although eight of the 11 studies agreed that SU’s reduce HbA1c, there were some limitations in their design. Of the eight, seven studies Muskiet et al. (2020), Hollander et al. (2017) Hassan and Abd-Allah (2015, Leiter et al. (2015), Del Prato et al. (2014), Nauck et al. (2014) and Nauck et al. (2011) used a randomised control trial design (RCT). One study by Gillani et al. (2022) used a cohort study design. Using a Robust RCT design, enhances the validity of the results by providing a rigorous tool to test relationships between intervention, the design reduces the play of external factors influencing the outcome [4,9,11,10,13,14,18].

Muskiet et al. (2020) and Hassan and Abd-Allah (2015) used small sample sizes N=46 and N=180 respectively. Both studies also used short study periods, Muskiet et al. (2020) only eight weeks, and Abd-Allah (2015) assessed outcome at 3 months. Additionally, the sample only included males, meaning that the sample was not representative, which limits the generalisations that can be made from the results. Larger sample sizes and longer study periods could have been utilised to increase the validity and reliability [11,17]. The study by Gillani et al. (2022) may have introduced bias, as there was no mention of dosage of each medication used. Potentially, the interventions may have been different which could have introduced performance bias. Additionally, confounders may have had a role to play, as compliance with trial medication may have affected the results [4].

Theme Three - Changes in Body Weight

Of the eleven studies, seven by Gillani et al. (2022), Muskiet et al. (2020), Hollander et al [4,14,17]. Assessed body mass/weight in 8,745 participants. All established that SU and metformin combination was associated with weight gain [8,9,10,13].

Metformin and Su Combination

All seven studies established that SU and metformin combination was associated with weight gain. Gillani et al. (2022) found an increase of + 0.87kg, Muskiet et al. (2020) +0.8 increase with glimepiride, Hollander et al. (2017) + 0.9kg with glipizide, Leiter et al. (2015) + 0.8kg with glimepiride, Del Prato et al. (2014) + 0.95 kg for glipizide, Nauck et al. (2014) and Nauck et al. (2011) found a 1.4kg increase glipizide. A combined weight gain of 5.72kg for SU and metformin [4,8,13,17].

Metformin and DPP4i

Of the seven studies, three compared SU and metformin to DPP4i. All 3 studies concurred that DPP4i was linked to weight loss. Gillani et al. (2022) found a -2.2kg weight loss with DPP4i, Muskiet et al. (2020) a 0.5kg weight loss with Linagliptin and Del Prato et al. (2014) -0.68 and -0.89 loss with Alogliptin. A combined weight loss of -4.27kg for DPP4i [4,17].

Metformin and SGLT2i

Four of the seven studies measuring weight/body mass, assessed the performance of SU’s and metformin against SGLT2i. Hollander et al. (2017) found in the two ertugliflozin groups, a loss of - 3.4kg and -3.0kg. Leiter et al. (2015) found a loss of 3.6kg and 3.6kg in both canagliflozin groups. Nauck et al. (2014) and Nauck et al. (2011) demonstrated a -3.4kg and -3.7kg at the end of the studies [14,8,9,13].

A combined loss of -20.7kg. Here, all seven studies agreed that SU’s are associated with weight gain, with a combined weight gain of over 5.72kg. In contrast, SGLT2i’ and DPP4i’s showed significant weight reduction versus SU, -20.7kg and 4.27kg respectively. Overall SGLT2i’s provided a greater weight reduction than DPP4i’s. The findings are parallel to those of a systematic review and meta-analysis by Storgaard et al. (2016). They concluded that SGLT2i’s had a greater weight loss when compared to DPP4i and Sulfonylurea. In their study, sulfonylurea was also shown to cause increased weight gain. Storgaard et al. (2016) suggests SGLT2’s is a safe and effective alternative to SU’s, and that the reduction in body weight, lipid profiles and systolic blood pressure identified from the findings, may have a positive impact on the reduction of cardiovascular risk [18].

Gillani et al. (2022), included only newly diabetic patients, this means patients with more advanced disease were excluded [4]. This limits the generalisations that could be made from the results and indicates potential selection bias. Including patients with different stages of the disease would have increased the representativeness of the sample. Hollander et al. (2017) and Del Prato et al. (2014) performed a power calculation, which was met, thus adding validity to the study. In contrast, Leiter et al. (2015) did not. A power calculation would ensure enough participants were enrolled to see a true effect [14,10,8].

Seven of the studies by Gillani et al. (2022), Muskiet et al. (2020), Hollander et al. (2017), Leiter et al. (2015), Del Prato et al. (2014), Nauck et al. (2014) and Nauck et al. (2011) did not monitor the participants calorie intake or diet which could have impacted the outcomes [4,17,14,8,10,9,13]. Nauck et al. (2014) Nauck et al. (2011) conducted the studies internationally, including 16 UK centres, making the results more applicable and increases generalisability [9,19].

Conclusion

Whilst metformin and sulfonylureas remain an effective second line treatment option for type 2 diabetes by reducing HbA1c levels. The review emphasized that SU’s are associated with weight gain, and cardiovascular risk remains unclear. SGLT2i’s are concomitant with a reduction in body weight, with a more sustained lowering of HbA1c over time and blood pressure lowering. SGLT2i’s are a safe and effective alternative to SU as they may provide cardiovascular protection. An individualised holistic assessment of patients should be carried out to determine the cardiovascular risk, and regular reviews of antidiabetic medication should be carried out to ensure they are updated to suit the patient’s needs. More robust research is needed to further examine combination oral antidiabetic treatments and cardiovascular risk, as there was a high level of heterogeneity (I2) and bias between the studies [20-30].

Figure 1: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. 2021.

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71

Table 1: Characteristics of included studies

References

1. Holt, R.I.G., Cockram, C.S., Flyvbjerg, A., Goldstein, B.J. (2017) Textbook of Diabetes. 5th ed. [online]. John Wiley & Sons, Ltd. Available at: ProQuest Ebook Central - Reader [Accessed: 28 December, 2022].
2. Valaiyapathi, B., Gower, B., & Ashraf, A. P. (2020). Pathophysiology of type 2 diabetes in children and adolescents. Current diabetes reviews, 16(3), 220-229.
3. Ghosh, S., & Collier, A. (2012). Churchill's Pocketbook of Diabetes E-Book. Elsevier Health Sciences.
4. Gillani, S.W., Sulaiman, S.A.S., Menon, V., Rahamathullah,I. N., Elshafie, R.M., Rathore H.A. (2022) Effect of different antidiabetic medications on atherosclerotic cardiovascular disease (ASCVD) risk score among patients with type-2 diabetes mellitus: A multicentre noninterventional observational study. Public Online Journal of Science, 17(6), 1-15
5. Wanga, J., Wua, H.Y., Chiena, K.L. (2021) Cardioprotective effects of dipeptidyl peptidase-4 inhibitors versus sulfonylureas in addition to metformin: A nationwide cohort study of patients with type 2 diabetes. Diabetes & Metabolism, 48(3), 1-9
6. Douros, A., Dell’ Aniello, S., Hoi Yun Yu, O., Filion, K., Azoulay. L., Suissa, S. (2018) Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population-based cohort study. British Medical Journal 36(2), 1-9
7. Chang, Y.C., Chuang, L.M., Lin, J.W., Chen. S.T., Lai, M.S., Chang, C.H. (2015) Cardiovascular risks associated with second-line oral antidiabetic agents added to metformin in patients with Type 2 diabetes: a nationwide cohort study, Diabetic Medicine, 32(11), 1397-1528
8. Leiter, L., Yoon, K.H., Arias, P., Langslet, G., Xie, J., Balis, D.A., Millington, D., Vercruysse, F., Canovatchel, W., Meininger, G. (2015) Canagliflozin Provides Durable Glycaemic Improvements and Body Weight Reduction Over 104 Weeks Versus Glimepiride in Patients with Type 2 Diabetes on Metformin: A Randomized, DoubleBlind, Phase 3 Study Diabetes Care, 38(3), 355–364
9. Nauck, M.A., Del Prato, S., Duran-Garcia, S., Rohwedder, K., Langkilde A.M., Sugg., Parikh, S.J. (2014) Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes, Obesity and Metabolism, 16(11)
10. Del Prato, S., Camisasca, R., Wilson, C., Fleck, P. (2014) Durability of the efficacy and safety of Alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-year study. Diabetes, Obesity and Metabolism, 16(12), 1239–124
11. Hassan, M.H., Abd-Allah, G.M. (2015) Effects of metformin plus  gliclazide  versus  metformin  plus  glimepiride  on cardiovascular risk factors in patients with type 2 diabetes mellitus. Pakistan Journal of Pharmaceutical Sciences, 49(1), 60-74
12. Pantalone, K.M., Kattan. M.W., Yu, C., Wells, B. J., Arrigain, S., Nutter, B., Jain, Atreja, A.A., Zimmerman, R.S. (2012) Treatment The risk of overall mortality in patients with Type 2 diabetes receiving different combinations of sulfonylureas and metformin: a retrospective analysis. Journal of Diabetic Medicine, 29(8), 1029-1035
13. Nauck, M.A., Del Prato, S., Meier, J.J., Duran- Garcia, S., Rohwedder, K., Elze, M., Parikh, S.J. (2011) Dapagliflozin Versus Glipizide as Add-on Therapy in Patients with Type 2 Diabetes Who Have Inadequate Glycaemic Control With Metformin A randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes, Obesity and Metabolism, 34(9), 2015–2022
14. Hollander, P., Liu, J., Hill, J., Johnson, J., Jiang. J.W., Golm.G., Huyck, S., Terra, S.G., Mancuso, J.P., Engel, S.S, Laurin,B. (2017) Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Therapy, 9,193–207
15. Chen, Z., & Li, G. (2019). Sodium-glucose co-transporter 2 inhibitors compared with sulfonylureas in patients with type 2 diabetes inadequately controlled on metformin: a meta-analysis of randomized controlled trials. Clinical drug investigation, 39, 521-531.
16. Deacon, C.F., Lebovitz, H.E. (2016) Comparative review of dipeptidyl peptidase-4 inhibitors and sulfonylureas. Diabetes, Obesity and Metabolism, 18(4) 334-347
17. Muskiet , M.H.A., Tonneijck, L., Smits, M.M., Kramer, M.H.H., Ouwens, D.M., Hartmann, B., Holst, J.J., Touw, D.J., Danser, H.J., Joles, J.A., Van Raalte, D.H. (2020) Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial. Diabetes Care, 43(11), 2889–2893
18. Storgaard, H., Gluud, L.L., Bennett, C., Grøndahl, M.F., Christensen, M.B., Knop, F.K., Vilsbøll, T. (2016) Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Public Library of Science ONE, 11(11), 1-23
19. Chen, Y.Y., Lin, Y.L., Chong1, E. Chen, P.C., Chao, T.F., Chen, S.A., Chien, K.L. (2015) The Impact of Diabetes Mellitus and Corresponding HbA1c Levels on the Future Risks of Cardiovascular Disease and Mortality: A Representative Cohort Study in Taiwan. PLOS one, 10(4), 1-12
20. A Meta-Analysis of Randomized Controlled Trials. Clinical Drug Investigation
21. Critical Appraisal Skills Programme (2020) CASP (Randomised Controlled Trial and Cohort Study) Checklist.
22. Diabetes UK (2019) Tackling the crisis: Transforming diabetes care for a better future England.
23. Diabetes.co.uk (2022) Insulin
24. Hariton, E., Locascio, J.J. (2018) Randomised controlled trials—the gold standard for effectiveness research. British journal of obstetrics and gynaecology, 125(13), 1-3
25. National Institute for Health and Care Excellence (NICE).(2022) How to choose medicines for further treatment.
26. National Institute for Health and Care Excellence (NICE). (2015) Putting NICE guidance into practice: Resource impact report: Type 2 diabetes in adults: management (update) NICE.
27. National Health Service (NHS). (2020) Understanding Medicine: Type 2 diabetes.
28. PRISMA. (2020) PRISMA 2020 Checklist.
29. Training, Research and Education for Nurses in Diabetes (TREND). (2022) For Healthcare Professionals: An Integrated Career and Competency Framework for Adult Diabetes Nursing. TREND. 6th ed.
30. World Health Organization (WHO). (2022) Diabetes: key