literature review of diabetic neuropathy

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• Published: June 2007

Diabetic neuropathy—a review

• Gérard Said 1  

Nature Clinical Practice Neurology volume  3 ,  pages 331–340 ( 2007 ) Cite this article

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Diabetic neuropathy is the most common neuropathy in industrialized countries, and it is associated with a wide range of clinical manifestations. The vast majority of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder that progresses following a fiber-length-dependent pattern, with sensory and autonomic manifestations predominating. This pattern of neuropathy is associated with a progressive distal axonopathy. Patients experience pain, trophic changes in the feet, and autonomic disturbances. Occasionally, patients with diabetes can develop focal and multifocal neuropathies that include cranial nerve involvement and limb and truncal neuropathies. This neuropathic pattern tends to occur after 50 years of age, and mostly in patients with long-standing diabetes mellitus. Length-dependent diabetic polyneuropathy does not show any trend towards improvement, and either relentlessly progresses or remains relatively stable over a number of years. Conversely, the focal diabetic neuropathies, which are often associated with inflammatory vasculopathy on nerve biopsies, remain self-limited, sometimes after a relapsing course.

Length-dependent peripheral neuropathy is a common complication of diabetes, and carries a high risk of pain, trophic changes and autonomic dysfunction

Optimum glycemic control is the best preventive treatment for diabetic neuropathy

Inflammatory lesions are common in focal and multifocal neuropathies

If motor deficit or proprioceptive involvement predominates, it is important to consider nondiabetic causes of neuropathy

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International Diabetes Federation [ http://www.idf.org/ ]

Pirart J (1978) Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1 : 168–188, 253–263

Article   Google Scholar  

Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329 : 977–986

Martin CL et al . (2006) Neuropathy among the Diabetes Control and Complications Trial Cohort 8 years after trial completion. Diabetes Care 29 : 340–344

Said G et al . (1998) Uncommon early onset neuropathy in diabetic patients. J Neurol 245 : 61–68

Article   CAS   Google Scholar  

Palumbo PJ et al . (1978) Neurologic complications of diabetic mellitus: transient ischemic attack, stroke and peripheral neuropathy. In Advances in Neurology , vol 19 , 593–601 (Ed Schoenberg BS) New York: Raven Press

Google Scholar  

De Freitas MRG et al . (1992) Diabetic neuropathy. I—epidemiology, classification, clinical and electrophysiological aspects. A study of 210 cases [Portuguese]. Rev Brasileira Neurol 28 : 69–73

Said G (1981) Progressive centripetal degeneration in polyneuropathies [French]. Rev Neurol 137 : 573–588

CAS   PubMed   Google Scholar  

Said G et al . (1983) Progressive centripetal degeneration of axons in small fibre type diabetic polyneuropathy: a clinical and pathological study. Brain 106 : 791–807

Guy RJC et al . (1985) Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia 28 : 131–137

Vergely P (1893) Sensory changes in the lower limbs in diabetic patients: syringomyelic dissociation of sensations in diabetic patients [French]. Gazette Hebdomadaire de Médecine et de Chirurgie 32 : 376–381

Shun CT et al . (2004) Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 127 : 1593–1605

Charcot JM (1890) A case of diabetic paraplegia [French]. Arch Neurol (Paris) 19 : 305–330

Andreassen CS et al . (2006) Muscle weakness—a progressive late complication in diabetic distal symmetric polyneuropathy. Diabetes 55 : 806–812

Cornblath D et al . (1987) Demyelinating motor neuropathy in patients with diabetic polyneuropathy. Ann Neurol 22 : 126–132

Pavy FW (1887) Address on diabetes, Washington International Congress. Med News (Philadelphia) 24 : 357–361

Brown MJ et al . (1976) Painful diabetic neuropathy: a morphological study. Arch Neurol 33 : 164–171

Llewelyn JG et al . (1991) Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. Brain 114 : 867–892

Sorensen L et al . (2006) The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 29 : 883–887

Orstavik K et al . (2006) Abnormal function of C-fibers in patients with diabetic neuropathy. J Neurosci 26 : 11287–11294

Waxman SG (2006) Neurobiology: a channel sets the gain on pain. Nature 444 : 831–832

Ellenberg M (1974) Diabetic neuropathic cachexia. Diabetes 23 : 418–423

Archer AG et al . (1983) The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 46 : 491–499

Said G (1980) Acrodystrophic neuropathies. Muscle Nerve 3 : 491–501

Landrieu P et al . (1990) Dominantly transmitted congenital indifference to pain. Ann Neurol 27 : 574–578

Shaw JE and Boulton AJM (1998) The pathogenesis of foot problems. In Contemporary Endocrinology: Management of Diabetic Neuropathy , 291–301 (Ed Veves A) Totowa, NJ: Humana Press

Chapter   Google Scholar  

Akbari CM and LoGerfo FW (1998) The impact of micro- and macrovascular disease on diabetic neuropathy and foot problems. In Contemporary Endocrinology: Management of Diabetic Neuropathy , 319–331 (Ed Veves A) Totowa, NJ: Humana Press

Llewelyn JG et al . (2005) Diabetic neuropathies. In Peripheral Neuropathy , vol 2 , 1951–1991 (Eds Dyck PJ and Thomas PK) Philadelphia: Elsevier Saunders

Vinik AI et al . (2003) Diabetic autonomic neuropathy. Diabetes Care 26 : 1553–1579

Dreyfus PM et al . (1957) Diabetic ophthalmoplegia; report of case, with postmortem study and comments on vascular supply of human oculomotor nerve. AMA Arch Neurol Psychiatry 77 : 337–349

Asbury AK et al . (1970) Oculomotor palsy in diabetes mellitus: a clinico-pathological study. Brain 93 : 555–566

Ellenberg M (1978) Diabetic truncal mononeuropathy: a new clinical syndrome. Diabetes Care 1 : 10–13

Stewart JD (1989) Diabetic truncal neuropathy: topography of the sensory deficit. Ann Neurol 25 : 233–238

Bruns L (1890) Neuropathic paralysis in diabetes mellitus [German]. Berl Klin Wochenschr 27 : 509–515

Said G and Thomas PK (1999) Proximal diabetic neuropathy. In Diabetic Neuropathy , 474–480 (Eds Dyck PJ and Thomas PK) Philadelphia: WB Saunders

Coppack SW and Watkins PJ (1991) The natural history of diabetic femoral neuropathy. QJ Med 79 : 307–313

CAS   Google Scholar  

Said G et al . (1994) Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 35 : 559–569

Said G et al . (2003) Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 126 : 376–385

Behse F et al . (1977) Nerve biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry 40 : 1072–1082

Malik RA et al . (2005) Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 48 : 578–585

Caselli A et al . (2006) Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction. J Neurol Neurosurg Psychiatry 77 : 927–932

Thamotharampillai K et al . (2006) Decline in neurophysiological function after 7 years in an adolescent diabetic cohort and the role of aldose reductase gene polymorphisms. Diabetes Care 29 : 2053–2057

Johnson PC et al . (1986) Pathogenesis of diabetic neuropathy. Ann Neurol 19 : 450–457

King RHM et al . (1989) Diabetic neuropathy: abnormalities of Schwann cells and perineurial basal laminae: implications for diabetic vasculopathy. Neuropathol Appl Neurobiol 15 : 339–355

Dyck PJ et al . (1986) Fibre loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19 : 425–439

Llewelyn JG et al . (1998) Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 245 : 159–165

Dyck PJ et al . (1999) Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 10 : 2113–2121

Said G et al . (1997) Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favourable outcome. Ann Neurol 41 : 762–770

Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444 : 860–867

Sumner CJ et al . (2003) The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60 : 108–111

Leinninger GM et al . (2006) Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy. Nat Clin Pract Neurol 2 : 620–628

King RH (2001) The role of glycation in the pathogenesis of diabetic polyneuropathy. Mol Pathol 54 : 400–408

CAS   PubMed   PubMed Central   Google Scholar  

Ziegler D et al . (2006) Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29 : 2365–2370

Lozeron P et al . (2002) Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol 249 : 569–575

Gorson KC and Ropper AH (2006) Additional causes for distal sensory polyneuropathy in diabetic patients. J Neurol Neurosurg Psychiatry 77 : 354–358

Mulder DW et al . (1961) The neuropathies associated with diabetes: a clinical and electromyographic study of 103 unselected diabetic patients. Neurology 11 : 275–284

PubMed   Google Scholar  

Daube JR (1987) Electrophysiologic testing in diabetic neuropathy. In Diabetic Neuropathy , 162–176 (Eds PJ Dyck et al .) Philadelphia: WB Saunders

Stewart JD et al . (1996) Chronic inflammatory demyelinating polyneuropathy (CIPD) in diabetics. J Neurol Sci 142 : 59–64

Vinik AI et al . (2006) Diabetic nerve conduction abnormalities in the primary care setting. Diabetes Technol Ther 8 : 654–662

Giurini JM et al . (1998) Management of the diabetic foot. In Contemporary Endocrinology: Management of Diabetic Neuropathy , 303–318 (Ed Veves A) Totowa, NJ: Humana Press

Navarro X et al . (1997) Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 42 : 727–736

Said G et al . (1992) Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. N Engl J Med 326 : 1257–1263

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Service de Neurologie, Centre Hospitalier Universitaire de Bicêtre, Université Paris-Sud, 94275 Le Kremlin Bicêtre, France [email protected]

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G Said is Professor of Neurology and Chief of the Neurology Service at the Bicêtre University Hospital, Paris, France.,

Gérard Said

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Said, G. Diabetic neuropathy—a review. Nat Rev Neurol 3 , 331–340 (2007). https://doi.org/10.1038/ncpneuro0504

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Received : 03 November 2006

Accepted : 04 April 2007

Issue Date : June 2007

DOI : https://doi.org/10.1038/ncpneuro0504

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Treatment of diabetic peripheral neuropathy: a review

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Maher R Khdour, Treatment of diabetic peripheral neuropathy: a review, Journal of Pharmacy and Pharmacology , Volume 72, Issue 7, July 2020, Pages 863–872, https://doi.org/10.1111/jphp.13241

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This review surveys current pharmacotherapies available for the treatment of diabetic peripheral neuropathy (DPN), emphasising their mechanisms of action.

A comprehensive literature review focusing on the ‘pharmacotherapy and treatment of diabetic peripheral neuropathy’ was conducted. The Database of International Pharmaceutical Abstracts, EMBASE, PubMed, OVID, Scopus, Google and Google Scholar were searched, and reference lists of relevant articles were also included.

Diabetic peripheral neuropathy is often inadequately treated, and the role of improving glycaemic control specifically in type-2 diabetes remains unclear. It is crucial to explore the mechanisms of action and effectiveness of available therapies. Major international clinical guidelines for the management of DPN recommend several symptomatic treatments. First-line therapies include tricyclic antidepressants, serotonin–noradrenaline reuptake inhibitors, and anticonvulsants that act on calcium channels. Other therapies include opioids and topical agents such as capsaicin and lidocaine. The objectives of this paper are to review current guidelines for the pharmacological management of DPN and to discuss research relevant to the further development of pharmacological recommendations for the treatment of diabetic neuropathy.

Diabetic neuropathy is a highly prevalent, disabling condition, the management of which is associated with significant costs. Evidence supports the use of specific anticonvulsants and antidepressants for pain management in patients with diabetic peripheral neuropathy. All current guidelines advise a personalised approach with a low-dose start that is tailored to the maximum response having the least side effects or adverse events.

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Max Ellenberg , Leo Krainer; Diabetic Neuropathy: Review of Literature and a Case Report with Post-mortem Findings. Diabetes 1 July 1959; 8 (4): 279–283. https://doi.org/10.2337/diab.8.4.279

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Analyzing diabetes detection and classification: a bibliometric review (2000–2023).

1. Introduction

2. materials and methods, 2.1. data finding using the prisma framework, 2.2. data mining tool, 2.3. performance analysis, 3. bibliometric performance analysis for diabetes detection and classification, 3.1. leading countries, authors, affiliations, and sources based on the number of publications, 3.1.1. most productive countries, 3.1.2. most relevant authors, 3.1.3. most relevant affiliations, 3.1.4. most relevant sources, 3.2. trend analysis, 3.2.1. word cloud of keywords, 3.2.2. growth of top 10 keywords of authors, 3.2.3. trending topics, 3.3. citation analysis, 3.3.1. most cited authors, 3.3.2. most cited sources, 4. science mapping, 4.1. network analysis, 4.2. collaboration network of countries, 4.3. co-citation network of journals, 4.4. collaboration network of institutions, 5. summary of performance analysis, 5.1. thematic evaluation, 5.2. three-field plot, 6. discussion, 7. conclusions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

• Alamro, H.; Bajic, V.; Macvanin, M.T.; Isenovic, E.R.; Gojobori, T.; Essack, M.; Gao, X. Type 2 Diabetes Mellitus and its comorbidity, Alzheimer’ s disease: Identifying critical microRNA using machine learning. Front. Endocrinol. 2023 , 13 , 1084656. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Saberi-Karimian, M.; Mansoori, A.; Bajgiran, M.M.; Sadat, Z.; Amir, H.; Elias, K.; Rad, S.; Mahmoudi, M.; Negar, Z.; Khorasani, Y.; et al. Data mining approaches for type 2 diabetes mellitus prediction using anthropometric measurements. J. Clin. Lab. Anal. 2022 , 37 , e24798. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hennebelle, A.; Materwala, H.; Ismail, L. ScienceDirect ScienceDirect HealthEdge: A Machine Learning-Based Smart Healthcare HealthEdge: A Machine Learning-Based Smart Healthcare Framework for Prediction of Type 2 Diabetes in an Integrated IoT, Framework for Prediction of Type 2 Diabetes in an integrated IoT, edge, and cloud computing system. Procedia Comput. Sci. 2023 , 220 , 331–338. [ Google Scholar ] [ CrossRef ]
• Uddin, J.; Ahamad, M.; Hoque, N.; Walid, A.A.; Aktar, S. A Comparison of Machine Learning Techniques for the Detection of Type-2 Diabetes Mellitus: Experiences from Bangladesh. Information 2023 , 14 , 376. [ Google Scholar ] [ CrossRef ]
• Devos, P. Bibliometric analysis of research relating to hypertension reported over the period 1997–2016. J. Hypertens. 2019 , 37 , 2116–2122. [ Google Scholar ] [ CrossRef ]
• Glynn, R.W.; Chin, J.Z.; Kerin, M.J.; Sweeney, K.J. Representation of Cancer in the Medical Literature—A Bibliometric Analysis. PLoS ONE 2010 , 5 , e13902. [ Google Scholar ] [ CrossRef ]
• Gronthy, U.U.; Biswas, U.; Tapu, S.; Samad, A. A Bibliometric Analysis on Arrhythmia Detection and Classification from 2005 to 2022. Diagnostics 2023 , 13 , 1732. [ Google Scholar ] [ CrossRef ]
• Farhat, T.; Mounir, Z.A. Research in Congenital Heart Disease: A Comparative Bibliometric Analysis Between Developing and Developed Countries. Pediatr. Cardiol. 2012 , 34 , 375–382. [ Google Scholar ] [ CrossRef ]
• Yin, J.; Wan, J.; Zhu, J.; Zhou, G.; Pan, Y.; Zhou, H. Global trends and prospects about inflammasomes in stroke: A bibliometric analysis. Chin. Med. 2021 , 16 , 53. [ Google Scholar ] [ CrossRef ]
• Zhang, Z.; Zhu, Y.; Wang, Q.; Chang, T.; Liu, C. Global Trends and Research Hotspots of Exercise for Intervening Diabetes: A Bibliometric Analysis. Front. Public Health 2022 , 10 , 902825. [ Google Scholar ] [ CrossRef ]
• Riddell, M.C.; Li, Z.; Beck, R.W.; Gal, R.L.; Jacobs, P.G.; Castle, J.R.; Gillingham, M.B.; Clements, M.; Patton, S.R.; Dassau, E.; et al. More Time in Glucose Range During Exercise Days than Sedentary Days in Adults Living with Type 1 Diabetes. Diabetes Technol. Ther. 2021 , 23 , 376–383. [ Google Scholar ] [ CrossRef ]
• Yardley, J.E.; Kenny, G.P.; Perkins, B.A.; Riddell, M.C.; Balaa, N.; Malcolm, J.; Boulay, P.; Khandwala, F.; Sigal, R.J. Resistance Versus Aerobic Exercise. Diabetes Care 2013 , 36 , 537–542. [ Google Scholar ] [ CrossRef ]
• Subramanian, S.; Mishra, S.; Patil, S.; Shaw, K.; Aghajari, E. Machine Learning Styles for Diabetic Retinopathy Detection: A Review and Bibliometric Analysis. Big Data Cogn. Comput. 2022 , 6 , 154. [ Google Scholar ] [ CrossRef ]
• Du, S.; Zheng, Y.; Zhang, Y.; Wang, M. The Last Decade Publications on Diabetic Peripheral Neuropathic Pain: A Bibliometric Analysis. Front. Mol. Neurosci. 2022 , 15 , 854000. [ Google Scholar ] [ CrossRef ]
• Tesfaye, S. Painful diabetic peripheral neuropathy: Consensus recommendations on diagnosis, assessment and management. Diabetes/Metab. Res. Rev. 2011 , 27 , 629–638. [ Google Scholar ] [ CrossRef ]
• Blakeman, K. Bibliometrics in a digital age: Help or hindrance. Sci. Prog. 2018 , 101 , 293–310. [ Google Scholar ] [ CrossRef ]
• Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Ioannidis, J.P.A.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. Annals of Internal Medicine Academia and Clinic The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and elaboration. Ann. Intern. Med. 2009 , 151 , W-65. [ Google Scholar ] [ CrossRef ]
• Aria, M.; Cuccurullo, C.; Package, T.; Comprehensive, T.; Mapping, S. Package ‘Bibliometrix’ R Topics Documented ; 2023. [ Google Scholar ]
• Chowdhury, N.H.; Bin, M.; Reaz, I.; Ali, S.H.; Ahmad, S.; Haque, F.; Bakar, A.A.A.; Arif, M.; Bhuiyan, S. Nomogram-Based Chronic Kidney Disease Prediction Model for Type 1 Diabetes Mellitus Patients Using Routine Pathological Data. J. Pers. Med. 2022 , 12 , 1507. [ Google Scholar ] [ CrossRef ]
• Chowdhury, N.H.; Bin, M.; Reaz, I.; Haque, F.; Ahmad, S.; Ali, S.H.; Bakar, A.A.A.; Arif, M.; Bhuiyan, S. Performance Analysis of Conventional Machine Learning Algorithms for Identification of Chronic Kidney Disease in Type 1 Diabetes Mellitus Patients. Diagnostics 2021 , 11 , 2267. [ Google Scholar ] [ CrossRef ]
• Haque, F.; Bin, M.; Reaz, I.; Chowdhury, M.E.H.; Hamid, S.; Ashrif, A.; Bakar, A.; Rahman, T.; Kobashi, S.; Dhawale, C.A.; et al. A nomogram-based diabetic sensorimotor polyneuropathy severity prediction using Michigan neuropathy screening instrumentations. Comput. Biol. Med. 2021 , 139 , 104954. [ Google Scholar ] [ CrossRef ]
• Khandakar, A.; Chowdhury, M.E.H.; Bin, M.; Reaz, I.; Hamid, S.; Hasan, A.; Kiranyaz, S.; Rahman, T.; Alfkey, R.; Ashrif, A.; et al. A machine learning model for early detection of diabetic foot using thermogram images. Comput. Biol. Med. 2021 , 137 , 104838. [ Google Scholar ] [ CrossRef ]
• Haque, F.; Reaz, M.B.I.; Chowdhury, M.E.H.; Ibrahim, M.; Malik, R.A.; Alhatou, M.; Kobashi, S.; Ara, I.; Ali, S.H.M.; Bakar, A.A.A.; et al. A Machine Learning-Based Severity Prediction Tool for the Michigan Neuropathy Screening Instrument. Diagnostics 2023 , 13 , 264. [ Google Scholar ] [ CrossRef ]
• Achari, A.E.; Jain, S.K. Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction. Int. J. Mol. Sci. 2017 , 18 , 1321. [ Google Scholar ] [ CrossRef ]
• Gupta, R.; Hussain, A.; Misra, A. Diabetes and COVID-19: Evidence, current status and unanswered research questions. Eur. J. Clin. Nutr. 2020 , 74 , 864–870. [ Google Scholar ] [ CrossRef ]
• Li, Y.; Teng, D.; Shi, X.; Qin, G.; Qin, Y.; Quan, H.; Shi, B.; Sun, H.; Ba, J.; Chen, B.; et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: National cross sectional study. BMJ 2020 , 369 , m997. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cuadros, D.F.; Li, J.; Musuka, G.; Awad, S.F. Spatial epidemiology of diabetes: Methods and insights. World J. Diabetes 2021 , 12 , 1042–1056. [ Google Scholar ] [ CrossRef ]
• Gulshan, V.; Peng, L.; Coram, M.; Stumpe, M.C.; Wu, D.; Narayanaswamy, A.; Venugopalan, S.; Widner, K.; Madams, T.; Cuadros, J.; et al. Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs. JAMA 2016 , 316 , 2402–2410. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rotroff, D.M.; Oki, N.O.; Liang, X.; Yee, S.W.; Motsinger-reif, A.A.; Giacomini, K.M.; Kaddurah-daouk, R. Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans. Front. Pharmacol. 2016 , 7 , 135. [ Google Scholar ] [ CrossRef ]
• Mega, C.; De Lemos, E.T.; Vala, H.; Fernandes, R.; Oliveira, J.; Mascarenhas-melo, F.; Teixeira, F. Diabetic Nephropathy Amelioration by a Low-Dose Sitagliptin in an Animal Model of Type 2 Diabetes (Zucker Diabetic Fatty Rat). Exp. Diabetes Res. 2011 , 2011 , 162092. [ Google Scholar ] [ CrossRef ]
• Odedra, D.; Samanta, S. O RIGINAL D ATA Computational Intelligence-Based Diagnosis Tool for the Detection of Prediabetes and Type 2 Diabetes in India. RDS 2012 , 9 , 55–62. [ Google Scholar ]
• Pawar, S.D.; Naik, J.D.; Prabhu, P.; Jatti, G.M.; Jadhav, S.B.; Radhe, B.K. Comparative evaluation of Indian Diabetes Risk Score and Finnish Diabetes Risk Score for predicting risk of diabetes mellitus type II: A teaching hospital—Based survey in Maharashtra. J. Fam. Med. Prim. Care 2017 , 6 , 120–125. [ Google Scholar ] [ CrossRef ]
• Naz, H.; Ahuja, S. Deep learning approach for diabetes prediction using PIMA Indian dataset. J. Diabetes Metab. Disord. 2020 , 19 , 391–403. [ Google Scholar ] [ CrossRef ]
• Mohan, V.; Deepa, R.; Deepa, M.; Somannavar, S.; Datta, M. A Simplified Indian Diabetes Risk Score for Screening for Undiagnosed Diabetic Subjects. J. Assoc. Physicians India 2005 , 53 , 759–763. [ Google Scholar ]
• Khandakar, A.; Chowdhury, M.E.H.; Bin, M.; Reaz, I.; Ali, S.H.; Kiranyaz, S.; Rahman, T.; Chowdhury, M.H.; Ayari, M.A. A Novel Machine Learning Approach for Severity Classification of Diabetic Foot Complications Using Thermogram Images. Sensors 2022 , 22 , 4249. [ Google Scholar ] [ CrossRef ]
• Gulshan, V.; Rajan, R.P.; Widner, K.; Wu, D.; Wubbels, P.; Rhodes, T.; Whitehouse, K.; Coram, M.; Corrado, G.; Ramasamy, K.; et al. Performance of a Deep-Learning Algorithm vs Manual Grading for Detecting Diabetic Retinopathy in India. JAMA Ophthalmol. 2019 , 137 , 987–993. [ Google Scholar ] [ CrossRef ]
• Krause, J.; Gulshan, V.; Rahimy, E.; Karth, P.; Widner, K.; Corrado, G.S.; Peng, L.; Webster, D.R. Grader Variability and the Importance of Reference Standards for Evaluating Machine Learning Models for Diabetic Retinopathy. Ophthalmology 2018 , 125 , 1264–1272. [ Google Scholar ] [ CrossRef ]
• Krishnamoorthy, G.; Ramakrishnan, J.; Devi, S. Bibliometric Analysis of Literature on Diabetes (1995–2004) ; CSIR: Delhi, India, 2009; Volume 5, pp. 150–155. [ Google Scholar ]
• Jabali, K.A.; Ashiq, M.; Ahmad, S.; Rehman, S.U. A Bibliometric Analysis of Research Productivity on Diabetes Modeling and DigitalCommons @ University of Nebraska—Lincoln A Bibliometric Analysis of Research Productivity on Diabetes Modeling and Artificial Pancreas 2001 to 2020. Libr. Philos. Pract. 2020 , 4305 . [ Google Scholar ]
• Sweileh, W.M.; Al-jabi, S.W.; Sawalha, A.F. From Middle Eastern Arab countries during the period Statistical Package for Social Sciences Kingdom of Saudi Arabia. Scientometrics 2014 , 101 , 819–832. [ Google Scholar ] [ CrossRef ]
• Okaiyeto, K.; Oguntibeju, O.O. Saudi Journal of Biological Sciences Trends in diabetes research outputs in South Africa over 30 years from 2010 to 2019: A bibliometric analysis. Saudi J. Biol. Sci. 2021 , 28 , 2914–2924. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Werfalli, M.; Engel, M.E.; Musekiwa, A.; Kengne, A.P.; Levitt, N.S. The prevalence of Type 2 Diabetes among older people In Africa: A Systematic The prevalence of type 2 diabetes among older peopl e in Africa: A systematic review. LANCET Diabetes Endocrinol. 2016 , 4 , 72–84. [ Google Scholar ] [ CrossRef ]
• Article, O. Bibliometric Analysis of Diabetes Research in Relation to the COVID-19 Pandemic. J. Diabetol. 2021 , 12 , 350–356. [ Google Scholar ]
• Khedkar, V.N.; Patel, S. Diabetes Prediction Using Machine learning: A Bibliometric Analysis DigitalCommons @ University of Nebraska—Lincoln Diabetes Prediction Using Machine learning: A Bibliometric Analysis ; Library Philosophy and Practice: Lincoln, NE, USA, 2021. [ Google Scholar ]

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Ferdaus, J.; Rochy, E.A.; Biswas, U.; Tiang, J.J.; Nahid, A.-A. Analyzing Diabetes Detection and Classification: A Bibliometric Review (2000–2023). Sensors 2024 , 24 , 5346. https://doi.org/10.3390/s24165346

Ferdaus J, Rochy EA, Biswas U, Tiang JJ, Nahid A-A. Analyzing Diabetes Detection and Classification: A Bibliometric Review (2000–2023). Sensors . 2024; 24(16):5346. https://doi.org/10.3390/s24165346

Ferdaus, Jannatul, Esmay Azam Rochy, Uzzal Biswas, Jun Jiat Tiang, and Abdullah-Al Nahid. 2024. "Analyzing Diabetes Detection and Classification: A Bibliometric Review (2000–2023)" Sensors 24, no. 16: 5346. https://doi.org/10.3390/s24165346

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Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management

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• Published: 19 August 2024

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• Kamlesh Khunti   ORCID: orcid.org/0000-0003-2343-7099 1 ,
• Francesco Zaccardi   ORCID: orcid.org/0000-0002-2636-6487 1 ,
• Aslam Amod 2 ,
• Vanita R. Aroda   ORCID: orcid.org/0000-0002-7706-4585 3 ,
• Pablo Aschner   ORCID: orcid.org/0000-0002-6860-3620 4 ,
• Stephen Colagiuri   ORCID: orcid.org/0000-0002-2398-4781 5 ,
• Viswanathan Mohan   ORCID: orcid.org/0000-0001-5038-6210 6 &
• Juliana C. N. Chan   ORCID: orcid.org/0000-0003-1325-1194 7  

A panel of primary care and diabetes specialists conducted focused literature searches on the current role of glycaemic control in the management of type 2 diabetes and revisited the evolution of evidence supporting the importance of early and intensive blood glucose control as a central strategy to reduce the risk of adverse long-term outcomes. The optimal approach to type 2 diabetes management has evolved over time as the evidence base has expanded from data from trials that established the role of optimising glycaemic control to recent data from cardiovascular outcomes trials (CVOTs) demonstrating organ-protective effects of newer glucose-lowering drugs (GLDs). The results from these CVOTs were derived mainly from people with type 2 diabetes and prior cardiovascular and kidney disease or multiple risk factors. In more recent years, earlier diagnosis in high-risk individuals has contributed to the large proportion of people with type 2 diabetes who do not have complications. In these individuals, a legacy effect of early and optimal control of blood glucose and cardiometabolic risk factors has been proven to reduce cardiovascular and kidney disease events and all-cause mortality. As there is a lack of RCTs investigating the potential synergistic effects of intensive glucose control and organ-protective effects of newer GLDs, this article re-evaluates the evolution of the scientific evidence and highlights the importance of integrating glycaemic control as a pivotal early therapeutic goal in most people with type 2 diabetes, while targeting existing cardiovascular and kidney disease. We also emphasise the importance of implementing multifactorial management using a multidisciplinary approach to facilitate regular review, patient empowerment and the possibility of tailoring interventions to account for the heterogeneity of type 2 diabetes.

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Introduction

During the last four decades, the number of available diabetes treatments has more than tripled. Accordingly, clinical guidelines for type 2 diabetes management have evolved from approaches focusing on glycaemic control to more holistic and individualised approaches. The 2018 ADA/EASD recommendations represented a ‘paradigm shift’ in type 2 diabetes management [ 1 ], from a primary focus on control of hyperglycaemia to a focus on therapies with specific cardiorenal protective effects without primary consideration of glucose lowering in subsets of individuals. As a result, cardiorenal protection ranks alongside glycaemic control as a key treatment target (Fig. 1 a). This approach was based on the results from cardiovascular safety trials, mandated by the US Food and Drug Administration (FDA) since 2008 in response to the increased risk of myocardial infarction (MI) noted with rosiglitazone [ 2 ]. This required RCTs to demonstrate non-inferiority for cardiovascular outcomes when comparing newer glucose-lowering drugs (GLDs) with placebo on top of the best standard of care.

Paradigms for managing type 2 diabetes and reducing diabetes-related complications based on ( a ) current consensus recommendations by the ADA/EASD [ 3 ] and ( b ) expert opinion of the authors

These post-FDA cardiovascular outcomes trials (CVOTs) enrolled individuals with (very) high cardiovascular risk profiles to facilitate the accrual of high outcome event rates (Table 1 ). While dipeptidyl peptidase-4 inhibitors (DPP4is) showed neutral cardiovascular effects, sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated cardiorenal benefits in individuals with existing complications or multiple risk factors. These results have led to their recommended use as second-line GLDs after metformin for organ protection in high-risk individuals [ 3 ].

Although the long-term cardiorenal effects of these newer GLDs in individuals without cardiorenal complications and/or with few cardiometabolic risk factors have been investigated in pharmacoepidemiological studies [ 4 ], there is a lack of long-term RCTs of newer agents. Of note, in US real-world studies, around 50% of participants had clinical profiles that fulfilled none of the inclusion criteria for RCTs investigating SGLT2is, and 67% did not meet ADA recommendations for use of SGLT2is or GLP-1 RAs [ 5 , 6 ]. Moreover, the absolute risk reduction for SGLT2is and GLP-1 RAs in the lower risk diabetes populations is quantitatively smaller, as the same relative hazard reduction (i.e. HR) translates into a smaller absolute risk reduction in individuals at lower risk [ 7 , 8 ]. These observations raise important questions regarding the benefit of these newer organ-protective GLDs compared with the strategy of optimising glycaemic control for the majority of people with type 2 diabetes without complications.

Notwithstanding the availability of over ten classes of GLDs and the increase in the global burden of type 2 diabetes [ 9 ], there appears to be a growing perception that glycaemic control is not as important as organ-specific therapies. It is timely, therefore, to revisit the evolution of evidence supporting the importance of early and intensive blood glucose control as a fundamental strategy to optimise long-term outcomes in people with type 2 diabetes (Fig. 1 b).

Eight international diabetes experts (the authors) met virtually and in person to consider the current role of glycaemic control in the management of type 2 diabetes. Individual authors researched and provided commentaries on issues related to perceived messages and practices among physicians and barriers to evidence-to-practice translation. The authors conducted focused literature searches and identified key questions. The present article summarises key aspects of glycaemic control in people with type 2 diabetes.

Glycaemic control and diabetes-related complications

Chronic hyperglycaemia is associated with micro- and macrovascular complications, reduced quality of life and premature mortality. The beneficial influence of glycaemic control on clinical outcomes has been shown in observational studies by the positive associations between blood glucose levels and several diabetes-related outcomes. In the UK Prospective Diabetes Study (UKPDS) 35, the incidence of complications was significantly associated with blood glucose levels, with each 10.9 mmol/mol (1%) reduction in updated mean HbA 1c linked to a 21% reduction in any diabetes-related endpoint, 21% reduction in diabetes-related deaths, 14% reduction in MI and 37% reduction in microvascular complications [ 10 ]. In the Swedish National Diabetes Register, an HbA 1c level outside the target range was the strongest predictor of acute MI and stroke [ 11 ]. Systematic reviews and meta-analysis have also indicated positive relationships between HbA 1c and risk of macrovascular outcomes and mortality [ 12 ].

Although the UKPDS RCT demonstrated that intensive glucose control reduced the risk of long-term micro- and macrovascular complications in people with recently diagnosed type 2 diabetes [ 13 ], three RCTs published between 2008 and 2009 showed different results in people with type 2 diabetes of long duration, the majority of whom had complications or risk factors. In the ACCORD trial, intensive glucose control increased the risk of CVD and related death [ 14 ]. In the ADVANCE trial, a more gradual approach to achieving glycaemic targets reduced the risk of the predefined combined microvascular and macrovascular outcomes [ 15 ]. In the VA Diabetes Trials, intensive glucose control did not reduce the risk of CVD, microvascular outcomes, CVD death or all-cause death [ 16 ]. Post hoc analyses generated several hypotheses around the possible reasons for this. These included a lower efficacy of intensive glucose control in older people, the presence of complications (particularly autonomic neuropathy), the risk of hypoglycaemia with intensive treatment strategies and possibly higher rates of hypoglycaemia-associated complications [ 16 ]. At the same time meta-analyses of RCTs have confirmed that intensive glucose control reduces the risk of CVD, retinopathy and nephropathy [ 17 , 18 , 19 , 20 ]. In this light, microvascular complications have been conclusively proven to be prevented or delayed by optimal glycaemic control in people with type 1 and type 2 diabetes [ 16 , 19 ], emphasising the importance of glycaemic control as a key strategy in diabetes management.

The importance of early glycaemic control was first demonstrated in the UKPDS, in which tight control from diagnosis of type 2 diabetes reduced the MI and mortality risk 10 years later by 19–20%. In contrast, delaying glycaemic control reduced the mortality and MI risk by only 3% and 6.5%, respectively [ 21 ]. These ‘legacy effects’ became increasingly evident with prolonged follow-up. In the latest 44-year analysis of the UKPDS, early reduction of HbA 1c by 8.7 mmol/mol (0.8%) translated to a 10% risk reduction in diabetes-related endpoints, 17% risk reduction in MI, 26% risk reduction in microvascular complications and 10% risk reduction in mortality in the intensive treatment group compared with the control group [ 13 ]. As only a few participants in the UKPDS had CVD at baseline, a longer follow-up (i.e. more events) was required to accrue endpoints to achieve statistical significance [ 22 ]. Because the sample size and length of follow-up of a trial are dictated by the event rate (i.e. the risk of outcome occurrence), RCTs aiming for a ‘statistically significant’ result should last for several years, potentially decades, if low-risk participants have been enrolled; alternatively, longer term effects can be modelled based on the available data [ 23 , 24 , 25 ].

Recognising the heterogeneity of type 2 diabetes to improve diagnosis and management

With increasing knowledge about the pathophysiology of diabetes, matching key abnormal pathways with drug mechanisms to personalise care may be the way forward compared with a ‘one size fits all’ strategy.

Age is one key aspect underpinning diabetes phenotypes. Young-onset diabetes has complex aetiologies, with both leanness and obesity being equally important, especially in non-European populations [ 26 , 27 , 28 ]. Epidemiological analyses have revealed an inverse association between age at diagnosis and increased risk of micro- and macrovascular complications and mortality [ 27 ], with earlier diagnosis of type 2 diabetes having a greater impact on life expectancy than late-onset type 2 diabetes [ 29 ]. The association between age at diagnosis and risk of mortality/complications is probably due to the cumulative effects of hyperglycaemia and other risk factors in addition to host-related factors, such as genetics or perinatal development [ 28 , 30 ]. These data emphasise the importance of early and intensive treatment in young people with diabetes [ 27 ]. However, most RCTs (including CVOTs) have excluded younger individuals in order to attain a prespecified number of endpoints within a short period of time (i.e. greater statistical power). The lack of guidance has meant that these younger individuals are managed in a diverse manner in real-world practice, which might contribute to their poor outcomes.

The evidence is more robust in older individuals. Intensive glycaemic control is generally associated with a reduced risk of micro- and macrovascular complications, although benefits are attenuated with increasing age [ 11 ]. Treatment decisions in older people are more complex because of comorbidities, polypharmacy, frailty and cognitive dysfunction, and the benefits of intensive glycaemic control may be offset by the risk of adverse events, notably severe hypoglycaemia and falls [ 31 , 32 ]. There is now consensus that glycaemic goals should be individualised with less stringent glycaemic targets in this group and that GLDs that are associated with a low risk of hypoglycaemia should be used [ 33 ]. Over-treatment to achieve stringent glycaemic goals may increase the risk of mortality in older people on insulins, sulfonylureas or glinides [ 34 ].

Alongside age, information on HbA 1c , lipid profiles, autoantibodies, BMI, beta cell function, insulin resistance, genomics and gene expression have been variably included in models to cluster diabetes phenotypes [ 35 ]. For example, by using age, BMI, autoantibodies and markers of beta cell function and insulin resistance, individuals can be classified into five subtypes that predict insulin requirements and risk of chronic kidney disease (CKD). However, although these clusters have been replicated in European, Chinese and Indian populations, their clinical relevance has yet to be validated in other populations [ 36 , 37 , 38 ]. In addition, definitive evidence is needed on whether these complex clustering approaches are superior to conventional clinical and biochemical markers in informing practice [ 35 , 39 ]. However, given the estimated 5% prevalence of slowly evolving autoimmune type 1 diabetes masking as type 2 diabetes, standardised measurement of autoantibodies may enable insulin-insufficient individuals to be identified, avoiding undue delays in insulin initiation [ 40 , 41 ]. In support of this, variations in treatment effect across different phenotypes of type 2 diabetes have been reported in observational studies and post hoc analyses of RCTs [ 42 ]. However, pragmatic studies, ideally randomised, are needed to determine whether information on diagnostic phenotypes can be translated into therapeutic actions to improve the precision and cost-effectiveness of treatment [ 43 ].

Impact of CVOTs on the management paradigm for type 2 diabetes

During the last few decades, a wealth of evidence has emerged from CVOTs that supports the cardiorenal protective effects of SGLT2is and GLP-1 RAs in individuals with or at (very) high risk of CVD. Such benefits are mostly independent of intensive glycaemic control and some have also been observed in people without type 2 diabetes [ 44 , 45 , 46 ]. These results have created a paradigm shift to a focus on organ protection with less emphasis on glycaemic control, which may have had unintended consequences for the many individuals with poor glycaemic control who do not yet have complications [ 3 , 47 ]. The CVOTs included participants with CVD or multiple CVD risk factors in order to show safety first and, if demonstrated, efficacy [ 48 ] (Table 1 ); thus, they may not be generalisable to the wider type 2 diabetes population in routine clinical practice.

Meta-regression and subgroup analyses of CVOTs have reported similar or heterogeneous RR reductions in primary outcomes or in components of cardiorenal endpoints with SGLT2is and GLP-1 RAs when comparing individuals with vs individuals without, or with different severities of, CVD or CKD [ 7 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. Furthermore, given the low rate of events in individuals without complications, the same RR reduction translates to a very different absolute risk reduction, number needed to treat and cost-effectiveness [ 8 ]. These nuances highlight the need to perform baseline risk assessments to quantify the absolute benefits of SGLT2is and GLP-1 RAs. In this respect, the GRADE trial, which included participants with short-duration type 2 diabetes (<10 years) and HbA 1c levels of 51–69 mmol/mol (6.8–8.5%), showed that glargine and a GLP1-RA (liraglutide) were modestly better than a sulfonylurea (glimepiride) and DPP4i (sitagliptin) in reducing HbA 1c , although all four interventions improved glucose levels [ 56 ]. More RCTs and real-world evidence are required to assess the absolute benefits of the different GLD classes in low-risk individuals with short disease duration (see Text box: ‘Current evidence gaps and avenues for future research’).

In all placebo-controlled CVOTs, participants in the active treatment groups achieved lower HbA 1c than those in the control groups, suggesting that glycaemic control might have contributed to the positive outcomes [ 51 , 57 , 58 ] (Table 1 ). A post hoc analysis of the LEADER trial (which compared the risk of major adverse cardiovascular events [MACE] between liraglutide and placebo) suggested that up to 41% and 83% of the cardiovascular benefits of liraglutide (depending on the statistical method used) were mediated by a reduction in HbA 1c [ 57 ]. On the other hand, a mediation analysis of the EMPA-REG OUTCOME trial (which compared the risk of MACE between empagliflozin and placebo) identified haematocrit markers as potential mediators, with a smaller mediating role of glycaemic control, in line with the mechanisms of action of SGLT2is in regulating sodium and water metabolism [ 59 ]. A meta-regression of CVOTs estimated that if a 9.8 mmol/mol (0.9% ) reduction in HbA 1c was achieved instead of the observed mean of ~0.4% (~4.4 mmol/mol), the reduction in MACE would have been approximately 33%. These findings argue that glycaemic control may contribute, to a variable extent, to the effects of SGTL2is and GLP-1 RAs on MACE [ 51 ]. Furthermore, real-world data suggest that different cardiometabolic risk factors might be related to different clinical outcomes. For example, lipid and BP levels might have a greater effect size on MI/ischaemic heart disease, while body weight and glycaemic control might be more relevant for stroke, heart failure and kidney disease [ 60 , 61 ]. In the CVOTs of DPP-4is, GLP-1RAs and SGLT2is, the risk reduction in non-fatal stroke was entirely driven by glycaemic control [ 62 ]. Taken together, there is a need to gather more evidence to study the cost-effectiveness across all available GLDs of improving individual outcomes, especially in those without complications, guided by their baseline risk factors (see Text box: ‘Current evidence gaps and avenues for future research’).

In a typical primary care setting, only one-third of people with type 2 diabetes have CVD [ 63 ]. For those without CVD, physicians have a clear window of opportunity to focus on achieving and maintaining optimal glycaemic control alongside the control of CVD risk factors to prevent organ damage. Moreover, hyperglycaemia is a causal factor for microvascular complications, which is associated with poor quality of life and increased risk of CVD, for which optimal glycaemic control remains a definitive solution [ 64 , 65 ].

Glycaemic control as part of holistic multifactorial risk factor management

The overall goals of care in all people with type 2 diabetes centre on minimising the disease burden by reducing complications and premature mortality while maximising quality of life. This is achieved through the provision of personalised, evidence-based, cost-effective, accessible and affordable holistic interventions to improve blood glucose levels and risk factor control. Therapeutic strategies should aim for intensive glucose lowering to achieve personalised glycaemic targets, especially in people with early type 2 diabetes who do not have complications, rather than being based exclusively on organ-protective effects.

Traditional drugs such as metformin, sulfonylureas and DPP4is have proven glucose-lowering efficacy in RCTs and are well tolerated in real-world settings. Combination therapy can be used to achieve early and sustained optimal glycaemic control instead of the more common stepwise introduction of additional therapies. The VERIFY RCT demonstrated that early combination of metformin and a DPP4i delayed treatment escalation compared with incremental use of medications [ 66 ]. Similarly, population-based real-world evidence showed that early treatment escalation with DDP4is (within 2 years of diagnosis) on a background of metformin and sulfonylurea was associated with a delay in insulin initiation and a reduction in cardiorenal events and all-cause death [ 67 , 68 ].

It is important to note that, in the CVOTs of newer GLDs, including SGLT2is and GLP-1RAs, most participants were treated with conventional GLDs as well as renin–angiotensin–aldosterone system inhibitors, statins and antiplatelet therapy. The clustering of type 2 diabetes with other cardiometabolic risk factors emphasises the need for multifactorial risk factor management. In the Steno-2 study, intensive risk factor management (blood glucose, BP, lipids) with medications and lifestyle changes (smoking cessation) not only reduced the risk of microvascular complications but also translated into long-term reductions in cardiorenal events and mortality risk [ 69 , 70 , 71 ]. Several other studies have provided convincing evidence that intensive control of multiple risk factors reduces cardiorenal endpoints and mortality risk at all stages of diabetes [ 72 , 73 , 74 ].

People with type 2 diabetes have diverse needs beyond medical multifactorial risk management. The latest ADA/EASD guidelines [ 3 ] highlight the importance of identifying social determinants of health, including socioeconomic status, physical environment, food insecurity/access, healthcare access, affordability and quality, and social context [ 75 ]. While some of these factors might not be modifiable, clinicians are in a position to advocate and engage relevant stakeholders to provide holistic care to address the physical, mental, behavioural and social needs of their patients and improve their outcomes. As holistic, patient-centred and value-based care is context-dependent, using a multidisciplinary team approach is an effective strategy to address the multiple needs of people with diabetes. The allied healthcare professionals/workers making up such teams provide the much-needed liaison between patients and doctors to improve communication and relationships [ 76 ]. With the increasing use of electronic medical records, the systematic and ongoing collection of data by establishing well-designed registers that document upstream and modifiable risk factors, with regular linkage to medications, laboratory results, hospitalisations and deaths, can be extremely valuable. This can help inform decisions at both personal (patients and practitioners) and policy levels to improve system- and personal-level healthcare delivery aimed at reducing the burden of diabetes and its complications [ 77 ].

Unanswered questions regarding the generalised use of new GLDs

With the growing burden of type 2 diabetes in emerging countries, the choice of GLDs should also be considered in the context of available resources. Although generic SGLT2is are beginning to be available, newer SGLT2is and GLP-1 RAs continue to emerge that are significantly more expensive than traditional GLDs. In these circumstances, GLDs with long-established effectiveness, safety and affordability remain important therapeutic options [ 78 ].

In individuals with established complications, organ-protective SGLT2is and GLP-1 RAs reduce the risk of cardiorenal outcomes [ 79 ]; however, their effects on microvascular complications, notably neuropathy and retinopathy, have not been extensively explored [ 44 ]. Moreover, their efficacy against individual components of MACE is not uniform: while GLP-1 RAs reduce the risk of stroke [ 80 , 81 ], SGLT2is mainly reduce the risk of hospitalisations for heart failure and the risk of adverse kidney outcomes [ 51 , 52 , 79 , 81 , 82 , 83 ]. Furthermore, the effect size of GLP-1 RAs and SGLT2is for various outcomes differs within the same class of drugs and varies according to individual risk profiles [ 84 , 85 ]. Although these observations suggest the potential complementary beneficial effects of these two drug classes, the cost-effectiveness of this combination compared with early attainment of multiple treatment goals remains to be confirmed [ 25 , 86 , 87 ].

All GLDs are effective in reducing HbA 1c , with baseline HbA 1c being the main determinant of the reduction [ 88 ]. However, for all GLDs there is considerable variation in the magnitude of effect between and within drugs classes [ 7 , 81 , 89 , 90 , 91 , 92 , 93 , 94 ]. Similarly, the different mechanisms of actions of GLDs result in different safety profiles, both within and between drug classes. These include increased risk of hypoglycaemia (potentially life-threatening) for sulfonylureas and insulin [ 95 , 96 ], gastrointestinal side effects for GLP1-RAs [ 89 , 97 ], urogenital sepsis for SGLT2is [ 90 , 97 ], and heart failure and altered bone metabolism for thiazolidinediones [ 98 ]. Further head-to-head RCTs are required to better elucidate the efficacy/safety profiles of these medications and guide decisions based on the overall drug profiles and individuals’ concurrent metabolic abnormalities to maximise efficacy and minimise harm, while taking into consideration individual preference and affordability.

Barriers to improving type 2 diabetes management

Optimal glycaemic control remains a universal care gap. A systematic review of observational studies published between 2020 and 2022 reported that 45–93% of people with type 2 diabetes had poor glycaemic control, with considerable inter- and within-country variations [ 99 ]. These variations may be due to many factors, such as late diagnosis, delayed intervention, suboptimal self-management and limited access to care and effective treatments. In this light, glycaemic control has not improved over time despite the introduction of many GLDs and diabetes technologies [ 100 ].

Compared with RCTs, the magnitude of the HbA 1c reduction achieved with GLDs is lower in real-world clinical practice [ 101 ]. Among the contributing factors, poor medication adherence accounts for approximately 70% of the discrepancy between RCTs and real-world settings (Table 2 ) [ 27 ]. Therapeutic inertia (i.e. the delay in initiating/modifying treatment) is a key barrier to optimal type 2 diabetes management; delaying treatment intensification means missed opportunity to reduce adverse clinical outcomes [ 102 ]. However, some strategies implemented at provider (i.e. measurement of inertia through audits), patient (i.e. reminders through text messaging) and system (i.e. structured education sessions) levels have resulted in a reduction in therapeutic inertia [ 103 ].

In low-/middle-income countries, the availability of, and access to, medications are also major barriers. In all countries, variations in the costs of drug acquisition and administration, differences in reimbursement schemes and irregularity in pricing means that even cheap generic medications can become unaffordable. The WHO includes metformin, sulfonylureas, insulin and SGLT2is in the list of essential medications. To this end, there is an urgent need for policymakers to align the interests of all stakeholders and implement context-relevant drug financing policies to ensure that individuals have access to these life-saving medications.

Conclusions

Despite the central importance of early glycaemic control to improving outcomes throughout the lifespan of people with diabetes, real-world data show that glycaemic control remains poor in most settings. Most people with diabetes will benefit from early achievement and maintenance of glycaemic control. In these individuals, all GLD classes have been demonstrated to be safe and effective in achieving glycaemic targets, especially if supported by a self-management programme with regular assessment and control of risk factors. In addition to improving glycaemic control, in individuals with or at (very) high risk of cardiorenal complications, early use of GLDs with organ-protective effects should be considered if accessible and affordable, although many people will still need additional GLDs and other therapies to achieve multiple treatment targets. Each person with diabetes has a unique profile, which calls for individualised and holistic management beyond medications. By reorganising settings, workforces and models of care, it is possible to exercise a team approach to gather data regularly and stratify risk, empower self-care, reduce therapeutic inertia and use available multiple tools effectively to improve long-term outcomes.

Abbreviations

Chronic kidney disease

Cardiovascular outcomes trial

Dipeptidyl peptidase-4 inhibitor

Food and Drug Administration

Glucose-lowering drug

Glucagon-like-peptide-1 receptor agonist

Major adverse cardiovascular events

Myocardial infarction

Sodium–glucose cotransporter 2 inhibitor

UK Prospective Diabetes Study

Davies MJ, D’Alessio DA, Fradkin J et al (2018) Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 61(12):2461–2498. https://doi.org/10.2337/dci18-0033

Article   PubMed   Google Scholar  

Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471. https://doi.org/10.1056/NEJMoa072761

Article   PubMed   CAS   Google Scholar  

Davies MJ, Aroda VR, Collins BS et al (2022) Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 65(12):1925–1966. https://doi.org/10.1007/s00125-022-05787-2

Article   PubMed   PubMed Central   CAS   Google Scholar  

Zaccardi F, Davies MJ, Khunti K (2020) The present and future scope of real-world evidence research in diabetes: what questions can and cannot be answered and what might be possible in the future? Diabetes Obes Metab 22(Suppl 3):21–34. https://doi.org/10.1111/dom.13929

Wittbrodt E, Chamberlain D, Arnold SV, Tang F, Kosiborod M (2019) Eligibility of patients with type 2 diabetes for sodium-glucose co-transporter-2 inhibitor cardiovascular outcomes trials: an assessment using the Diabetes Collaborative Registry. Diabetes Obes Metab 21(8):1985–1989. https://doi.org/10.1111/dom.13738

Colling C, Atlas SJ, Wexler DJ (2021) Application of 2021 American diabetes association glycemic treatment clinical practice recommendations in primary care. Diabetes Care 44(6):1443–1446. https://doi.org/10.2337/dc21-0013

Shi Q, Nong K, Vandvik PO et al (2023) Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 381:e074068. https://doi.org/10.1136/bmj-2022-074068

Article   PubMed   PubMed Central   Google Scholar  

Spiegelhalter D (2017) Risk and uncertainty communication. Annu Rev Stat Appl 4(1):31–60. https://doi.org/10.1146/annurev-statistics-010814-020148

Article   Google Scholar  

GBD 2021 Diabetes Collaborators (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402(10397):203–234. https://doi.org/10.1016/S0140-6736(23)01301-6

Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258):405–412. https://doi.org/10.1136/bmj.321.7258.405

Rawshani A, Rawshani A, Franzen S et al (2018) Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 379(7):633–644. https://doi.org/10.1056/NEJMoa1800256

Zhang Y, Hu G, Yuan Z, Chen L (2012) Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One 7(8):e42551. https://doi.org/10.1371/journal.pone.0042551

Adler AI, Coleman RL, Leal J, Whitely WN, Clarke P, Holman RR (2024) Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91). Lancet 404(10448):145–155. https://doi.org/10.1016/S0140-6736(24)00537-3

Gerstein HC, Miller ME, Byington RP et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358(24):2545–2559. https://doi.org/10.1056/NEJMoa0802743

Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358(24):2560–2572. https://doi.org/10.1056/NEJMoa0802987

Skyler JS, Bergenstal R, Bonow RO et al (2009) Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 32(1):187–192. https://doi.org/10.2337/dc08-9026

Turnbull FM, Abraira C, Anderson RJ et al (2009) Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52(11):2288–2298. https://doi.org/10.1007/s00125-009-1470-0

Sun S, Hisland L, Grenet G et al (2022) Reappraisal of the efficacy of intensive glycaemic control on microvascular complications in patients with type 2 diabetes: a meta-analysis of randomised control-trials. Therapie 77(4):413–423. https://doi.org/10.1016/j.therap.2021.10.002

Zoungas S, Arima H, Gerstein HC et al (2017) Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 5(6):431–437. https://doi.org/10.1016/S2213-8587(17)30104-3

Kunutsor SK, Balasubramanian VG, Zaccardi F et al (2024) Glycaemic control and macrovascular and microvascular outcomes: a systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes. Diabetes Obes Metab 26(6):2069–2081. https://doi.org/10.1111/dom.15511

Lind M, Imberg H, Coleman RL, Nerman O, Holman RR (2021) Historical HbA(1c) values may explain the type 2 diabetes legacy effect: UKPDS 88. Diabetes Care 44(10):2231–2237. https://doi.org/10.2337/dc20-2439

Cefalu WT, Kaul S, Gerstein HC et al (2018) Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors’ expert forum. Diabetes Care 41(1):14–31. https://doi.org/10.2337/dci17-0057

Gaudino M, Pocock S, Rockhold F, Bhatt DL (2023) Reporting extended follow-up in cardiovascular clinical trials. J Am Coll Cardiol 82(23):2246–2250. https://doi.org/10.1016/j.jacc.2023.09.827

Davies MJ, Kloecker DE, Webb DR, Khunti K, Zaccardi F (2020) Number needed to treat in cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists: a systematic review with temporal analysis. Diabetes Obes Metab 22(9):1670–1677. https://doi.org/10.1111/dom.14066

Neuen BL, Heerspink HJL, Vart P et al (2024) Estimated lifetime cardiovascular, kidney, and mortality benefits of combination treatment with SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal MRA compared with conventional care in patients with type 2 diabetes and albuminuria. Circulation 149(6):450–462. https://doi.org/10.1161/circulationaha.123.067584

Luk AO, Lau ES, So WY et al (2014) Prospective study on the incidences of cardiovascular-renal complications in Chinese patients with young-onset type 1 and type 2 diabetes. Diabetes Care 37(1):149–157. https://doi.org/10.2337/dc13-1336

Misra S, Ke C, Srinivasan S et al (2023) Current insights and emerging trends in early-onset type 2 diabetes. Lancet Diabetes Endocrinol 11(10):768–782. https://doi.org/10.1016/S2213-8587(23)00225-5

Chan JCN, Chow E, Kong A et al (2024) Multifaceted nature of young-onset diabetes-can genomic medicine improve the precision of diagnosis and management? J Transl Genet Genom 8:13–34. https://doi.org/10.20517/jtgg.2023.36

Article   CAS   Google Scholar  

Emerging Risk Factors Collaboration (2023) Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation. Lancet Diabetes Endocrinol 11(10):731–742. https://doi.org/10.1016/S2213-8587(23)00223-1

Nanayakkara N, Curtis AJ, Heritier S et al (2021) Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses. Diabetologia 64(2):275–287. https://doi.org/10.1007/s00125-020-05319-w

Lee AK, Juraschek SP, Windham BG et al (2020) Severe hypoglycemia and risk of falls in type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 43(9):2060–2065. https://doi.org/10.2337/dc20-0316

Hambling CE, Khunti K, Cos X et al (2019) Factors influencing safe glucose-lowering in older adults with type 2 diabetes: a PeRsOn-centred ApproaCh To IndiVidualisEd (PROACTIVE) glycemic goals for older people: a position statement of primary care diabetes Europe. Prim Care Diabetes 13(4):330–352. https://doi.org/10.1016/j.pcd.2018.12.005

Christiaens A, Henrard S, Zerah L, Dalleur O, Bourdel-Marchasson I, Boland B (2021) Individualisation of glycaemic management in older people with type 2 diabetes: a systematic review of clinical practice guidelines recommendations. Age Ageing 50(6):1935–1942. https://doi.org/10.1093/ageing/afab157

Christiaens A, Boland B, Germanidis M, Dalleur O, Henrard S (2020) Poor health status, inappropriate glucose-lowering therapy and high one-year mortality in geriatric patients with type 2 diabetes. BMC Geriatr 20(1):367. https://doi.org/10.1186/s12877-020-01780-9

Misra S, Wagner R, Ozkan B et al (2023) Precision subclassification of type 2 diabetes: a systematic review. Commun Med 3(1):138. https://doi.org/10.1038/s43856-023-00360-3

Ke C, Narayan KMV, Chan JCN, Jha P, Shah BR (2022) Pathophysiology, phenotypes and management of type 2 diabetes mellitus in Indian and Chinese populations. Nat Rev Endocrinol 18(7):413–432. https://doi.org/10.1038/s41574-022-00669-4

Ahlqvist E, Storm P, Karajamaki A et al (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6(5):361–369. https://doi.org/10.1016/S2213-8587(18)30051-2

Anjana RM, Baskar V, Nair ATN et al (2020) Novel subgroups of type 2 diabetes and their association with microvascular outcomes in an Asian Indian population: a data-driven cluster analysis: the INSPIRED study. BMJ Open Diabetes Res Care 8(1):e001506. https://doi.org/10.1136/bmjdrc-2020-001506

Dennis JM, Shields BM, Henley WE, Jones AG, Hattersley AT (2019) Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data. Lancet Diabetes Endocrinol 7(6):442–451. https://doi.org/10.1016/S2213-8587(19)30087-7

Fan B, Lim CKP, Poon EWM et al (2023) Differential associations of GAD Antibodies (GADA) and C-peptide with insulin initiation, glycemic responses, and severe hypoglycemia in patients diagnosed with type 2 diabetes. Diabetes Care 46(6):1282–1291. https://doi.org/10.2337/dc22-2301

Fan B, Wu H, Shi M et al (2022) Associations of the HOMA2-%B and HOMA2-IR with progression to diabetes and glycaemic deterioration in young and middle-aged Chinese. Diabetes Metab Res Rev 38(5):e3525. https://doi.org/10.1002/dmrr.3525

Herder C, Roden M (2022) A novel diabetes typology: towards precision diabetology from pathogenesis to treatment. Diabetologia 65(11):1770–1781. https://doi.org/10.1007/s00125-021-05625-x

Tobias DK, Merino J, Ahmad A et al (2023) Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine. Nat Med 29(10):2438–2457. https://doi.org/10.1038/s41591-023-02502-5

Kunutsor SK, Zaccardi F, Balasubramanian VG et al (2024) Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents. Diabetes Obes Metab 26(5):1837–1849. https://doi.org/10.1111/dom.15500

Tsai WC, Hsu SP, Chiu YL et al (2022) Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open 12(10):e060655. https://doi.org/10.1136/bmjopen-2021-060655

Leite AR, Angélico-Gonçalves A, Vasques-Nóvoa F et al (2022) Effect of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese adults without diabetes: A meta-analysis of placebo-controlled randomized trials. Diabetes Obes Metab 24(8):1676–1680. https://doi.org/10.1111/dom.14707

Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferovic PM, Wanner C (2022) Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol 21(1):144. https://doi.org/10.1186/s12933-022-01575-9

Zaccardi F, Kloecker DE, Khunti K, Davies MJ (2022) Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: systematic analysis of cardiorenal outcome trials in type 2 diabetes. Diabetes Obes Metab 24(8):1598–1606. https://doi.org/10.1111/dom.14735

Rodriguez-Valadez JM, Tahsin M, Fleischmann KE et al (2023) Cardiovascular and renal benefits of novel diabetes drugs by baseline cardiovascular risk: a systematic review, meta-analysis, and meta-regression. Diabetes Care 46(6):1300–1310. https://doi.org/10.2337/dc22-0772

Sattar N, Lee MMY, Kristensen SL et al (2021) Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9(10):653–662. https://doi.org/10.1016/S2213-8587(21)00203-5

Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K (2019) Glycemic control, preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta-analysis of cardiovascular outcome trials and intensive glucose control trials. J Am Heart Assoc 8(12):e012356. https://doi.org/10.1161/JAHA.119.012356

McGuire DK, Shih WJ, Cosentino F et al (2021) Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 6(2):148–158. https://doi.org/10.1001/jamacardio.2020.4511

Rahman H, Khan SU, Lone AN et al (2023) Sodium-glucose cotransporter-2 inhibitors and primary prevention of atherosclerotic cardiovascular disease: a meta-analysis of randomized trials and systematic review. J Am Heart Assoc 12(16):e030578. https://doi.org/10.1161/JAHA.123.030578

Mosenzon O, Wiviott SD, Heerspink HJL et al (2021) The effect of dapagliflozin on albuminuria in DECLARE-TIMI 58. Diabetes Care 44(8):1805–1815. https://doi.org/10.2337/dc21-0076

Mosenzon O, Raz I, Wiviott SD et al (2022) Dapagliflozin and prevention of kidney disease among patients with type 2 diabetes: post Hoc analyses from the DECLARE-TIMI 58 trial. Diabetes Care 45(10):2350–2359. https://doi.org/10.2337/dc22-0382

Nathan DM, Lachin JM, Balasubramanyam A et al (2022) Glycemia reduction in type 2 diabetes - glycemic outcomes. N Engl J Med 387(12):1063–1074. https://doi.org/10.1056/NEJMoa2200433

Buse JB, Bain SC, Mann JFE et al (2020) Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial. Diabetes Care 43(7):1546–1552. https://doi.org/10.2337/dc19-2251

Konig M, Riddle MC, Colhoun HM et al (2021) Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND. Cardiovasc Diabetol 20(1):194. https://doi.org/10.1186/s12933-021-01386-4

Inzucchi SE, Zinman B, Fitchett D et al (2018) How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41(2):356–363. https://doi.org/10.2337/dc17-1096

Yang X, So WY, Kong AP et al (2007) Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes Care 30(1):65–70. https://doi.org/10.2337/dc06-1273

Yang X, So WY, Kong AP et al (2008) Development and validation of a total coronary heart disease risk score in type 2 diabetes mellitus. Am J Cardiol 101(5):596–601. https://doi.org/10.1016/j.amjcard.2007.10.019

Maiorino MI, Longo M, Scappaticcio L et al (2021) Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression. Cardiovasc Diabetol 20(1):210. https://doi.org/10.1186/s12933-021-01401-8

Einarson TR, Acs A, Ludwig C, Panton UH (2018) Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol 17(1):83. https://doi.org/10.1186/s12933-018-0728-6

Lui JNM, Lau ESH, Yang A et al (2023) Temporal associations of diabetes-related complications with health-related quality of life decrements in Chinese patients with type 2 diabetes: a prospective study among 19 322 adults-Joint Asia Diabetes Evaluation (JADE) register (2007–2018). J Diabetes. https://doi.org/10.1111/1753-0407.13503

Brownrigg JR, Hughes CO, Burleigh D et al (2016) Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol 4(7):588–597. https://doi.org/10.1016/S2213-8587(16)30057-2

Matthews DR, Paldánius PM, Proot P, Chiang Y, Stumvoll M, Del Prato S (2019) Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 394(10208):1519–1529. https://doi.org/10.1016/s0140-6736(19)32131-2

Cheung JTK, Yang A, Wu H et al (2024) Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: a propensity score-matched cohort study. Diabetes Metab Res Rev 40(1):e3711. https://doi.org/10.1002/dmrr.3711

Cheung JTK, Yang A, Wu H et al (2024) Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability. Diabetes Obes Metab. https://doi.org/10.1111/dom.15662

Gaede P, Lund-Andersen H, Parving HH, Pedersen O (2008) Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 358(6):580–591. https://doi.org/10.1056/NEJMoa0706245

Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348(5):383–393. https://doi.org/10.1056/NEJMoa021778

Gaede P, Vedel P, Parving HH, Pedersen O (1999) Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353(9153):617–622. https://doi.org/10.1016/S0140-6736(98)07368-1

Chan JC, So WY, Yeung CY et al (2009) Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study. Diabetes Care 32(6):977–982. https://doi.org/10.2337/dc08-1908

Ueki K, Sasako T, Okazaki Y et al (2017) Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial. Lancet Diabetes Endocrinol 5(12):951–964. https://doi.org/10.1016/S2213-8587(17)30327-3

Sasso FC, Pafundi PC, Simeon V et al (2021) Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease. Cardiovasc Diabetol 20(1):145. https://doi.org/10.1186/s12933-021-01343-1

Hill-Briggs F, Adler NE, Berkowitz SA et al (2020) Social determinants of health and diabetes: a scientific review. Diabetes Care 44(1):258–279. https://doi.org/10.2337/dci20-0053

McGill M, Blonde L, Chan JCN et al (2017) The interdisciplinary team in type 2 diabetes management: challenges and best practice solutions from real-world scenarios. J Clin Transl Endocrinol 7:21–27. https://doi.org/10.1016/j.jcte.2016.12.001

Chan JCN, Lim LL, Luk AOY et al (2019) From Hong Kong diabetes register to JADE program to RAMP-DM for data-driven actions. Diabetes Care 42(11):2022–2031. https://doi.org/10.2337/dci19-0003

Mohan V, Khunti K, Chan SP et al (2020) Management of type 2 diabetes in developing countries: balancing optimal glycaemic control and outcomes with affordability and accessibility to treatment. Diabetes Ther 11(1):15–35. https://doi.org/10.1007/s13300-019-00733-9

Zelniker TA, Wiviott SD, Raz I et al (2019) SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393(10166):31–39. https://doi.org/10.1016/S0140-6736(18)32590-X

Sim R, Chong CW, Loganadan NK et al (2022) Comparative effectiveness of cardiovascular, renal and safety outcomes of second-line antidiabetic drugs use in people with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Diabet Med 39(3):e14780. https://doi.org/10.1111/dme.14780

Palmer SC, Tendal B, Mustafa RA et al (2021) Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 372:m4573. https://doi.org/10.1136/bmj.m4573

Arnott C, Li Q, Kang A et al (2020) Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc 9(3):e014908. https://doi.org/10.1161/JAHA.119.014908

Grenet G, Ribault S, Nguyen GB et al (2019) GLUcose COntrol safety & efficacy in type 2 DIabetes, a systematic review and NETwork meta-analysis. PLoS One 14(6):e0217701. https://doi.org/10.1371/journal.pone.0217701

Li S, Vandvik PO, Lytvyn L et al (2021) SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline. BMJ 373:n1091. https://doi.org/10.1136/bmj.n1091

Zhu J, Yu X, Zheng Y et al (2020) Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map. Lancet Diabetes Endocrinol 8(3):192–205. https://doi.org/10.1016/S2213-8587(19)30422-X

Neves JS, Borges-Canha M, Vasques-Nóvoa F et al (2023) GLP-1 receptor agonist therapy with and without SGLT2 inhibitors in patients with type 2 diabetes. J Am Coll Cardiol 82(6):517–525. https://doi.org/10.1016/j.jacc.2023.05.048

DeFronzo RA (2017) Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab 19(10):1353–1362. https://doi.org/10.1111/dom.12982

Maloney A, Rosenstock J, Fonseca V (2019) A model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes: comparison of treatment effects at therapeutic doses. Clin Pharmacol Ther 105(5):1213–1223. https://doi.org/10.1002/cpt.1307

Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ (2016) Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments: a systematic review and network meta-analysis. Ann Intern Med 164(2):102–113. https://doi.org/10.7326/M15-1432

Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ (2016) Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 18(8):783–794. https://doi.org/10.1111/dom.12670

Amod A (2020) The place of sulfonylureas in guidelines: why are there differences? Diabetes Ther 11(1):5–14. https://doi.org/10.1007/s13300-020-00811-3

Ahrén B (2007) DPP-4 inhibitors—clinical data and clinical implications. Diabetes Care 30(6):1344–1350

PubMed   Google Scholar  

Van Gaal L, Scheen AJ (2002) Are all glitazones the same? Diabetes Metab Res Rev 18(Suppl 2):S1-4

Yao H, Zhang A, Li D et al (2024) Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ 384:e076410. https://doi.org/10.1136/bmj-2023-076410

Inkster B, Zammitt NN, Frier BM (2012) Drug-induced hypoglycaemia in type 2 diabetes. Expert Opin Drug Saf 11(4):597–614. https://doi.org/10.1517/14740338.2012.694424

Andersen SE, Christensen M (2016) Hypoglycaemia when adding sulphonylurea to metformin: a systematic review and network meta-analysis. Br J Clin Pharmacol 82(5):1291–1302. https://doi.org/10.1111/bcp.13059

Hussein H, Zaccardi F, Khunti K et al (2020) Efficacy and tolerability of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis. Diabetes Obes Metab 22(7):1035–1046. https://doi.org/10.1111/dom.14008

Davidson MA, Mattison DR, Azoulay L, Krewski D (2018) Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit Rev Toxicol 48(1):52–108. https://doi.org/10.1080/10408444.2017.1351420

Bin Rakhis SA Sr., AlDuwayhis NM, Aleid N, AlBarrak AN, Aloraini AA (2022) Glycemic control for type 2 diabetes mellitus patients: a systematic review. Cureus 14(6):e26180. https://doi.org/10.7759/cureus.26180

Aschner P, Gagliardino JJ, Ilkova H et al (2020) Persistent poor glycaemic control in individuals with type 2 diabetes in developing countries: 12 years of real-world evidence of the International Diabetes Management Practices Study (IDMPS). Diabetologia 63(4):711–721. https://doi.org/10.1007/s00125-019-05078-3

Carls GS, Tuttle E, Tan RD et al (2017) Understanding the gap between efficacy in randomized controlled trials and effectiveness in real-world use of GLP-1 RA and DPP-4 therapies in patients with type 2 diabetes. Diabetes Care 40(11):1469–1478. https://doi.org/10.2337/dc16-2725

Paul SK, Klein K, Thorsted BL, Wolden ML, Khunti K (2015) Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol 14:100. https://doi.org/10.1186/s12933-015-0260-x

Khunti S, Khunti K, Seidu S (2019) Therapeutic inertia in type 2 diabetes: prevalence, causes, consequences and methods to overcome inertia. Ther Adv Endocrinol Metab 10:2042018819844694. https://doi.org/10.1177/2042018819844694

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Diabetes Research Centre, University of Leicester, Leicester, UK

Kamlesh Khunti & Francesco Zaccardi

Department of Endocrinology, Nelson Mandela School of Medicine and Life Chatsmed Garden Hospital, Durban, South Africa

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Vanita R. Aroda

Endocrinology Unit, Javeriana University and San Ignacio University Hospital, Bogotá, Colombia

Pablo Aschner

Boden Collaboration, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

Stephen Colagiuri

Department of Diabetology, Dr Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India

Viswanathan Mohan

Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

Juliana C. N. Chan

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Correspondence to Kamlesh Khunti or Francesco Zaccardi .

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We would like to thank C. Rees (New Zealand), who provided medical writing support in the early stages of manuscript development on behalf of Springer Healthcare.

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Medical writing support in the early stages of manuscript development, on behalf of Springer Healthcare, was funded by Servier.

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KK is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre (BRC) and has served as a consultant or speaker for, or received grants for investigator-initiated studies from AstraZeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche and Applied Therapeutics. FZ has received consulting fees from Daiichi Sankyo. VM has received research or educational grants from Abbott, Bayer, Boehringer Ingelheim, Eli Lilly, LifeScan, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, Servier, USV, Dr. Reddy’s, Sun Pharma, Intas, Lupin, Glenmark, Zydus, Ipca, Torrent, Cipla, Biocon, Primus, Franco-Indian, Wockhardt, Emcure, Mankind, Medtronic, Fourrts, Apex, GSK and Alembic. PA has received honoraria or consulting fees from Boehringer Ingelheim, Janssen, MSD, Novartis and Sanofi and has participated in company-sponsored speakers bureaus for Eli Lilly, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk and Sanofi. JCNC has received grants through her institutions and personal fees for consultancy and lectures from Astra Zeneca, Bayer, Boehringer Ingelheim, Hua Medicine, Eli Lilly, Merck, MSD, Powder Pharmaceuticals, Sanofi, Viatris and Zuellig Pharma outside the submitted work. SC has received an honorarium from Servier. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

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KK and JC participated in the conception of the review and performed the literature searches. All authors were involved in the planning of the manuscript and read and contributed to writing all drafts of the manuscript. All authors approved the final version to be published.

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Khunti, K., Zaccardi, F., Amod, A. et al. Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management. Diabetologia (2024). https://doi.org/10.1007/s00125-024-06254-w

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Diabetic cardiac autonomic neuropathy and anesthetic management: review of the literature

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• 1 University of Alabama at Birmingham School of Nurse Anesthesia, Birmingham, Alabama, USA.
• PMID: 22400413

Cardiac autonomic neuropathy is a serious complication among diabetic patients. It occurs in both type 1 and type 2 diabetes, and its progression results in poor prognosis and increased mortality. During its course, parasympathetic and sympathetic nerve fibers of the cardiovascular system are damaged, resulting in potentially serious cardiac complications and even death. Poor glycemic control is believed to play a pivotal role in the pathogenesis of cardiac autonomic neuropathy. Its underlying etiology is not well understood; however, several potential pathologic mechanisms have been identified. Several clinical manifestations of cardiac autonomic neuropathy have been reported, including resting tachycardia, exercise intolerance, loss of heart rate variability, orthostatic hypotension, prolonged QT interval, silent ischemia, and sudden death. Diabetic patients exhibiting these signs and symptoms are at greater risk of anesthesia-related complications. A series of noninvasive autonomic tests were developed for the diagnosis of cardiac autonomic neuropathy, improving the management of diabetic patients requiring general anesthesia. These patients often experience cardiovascular events that may increase perioperative morbidity and mortality. The presence of cardiac autonomic neuropathy alters the hemodynamic response to induction and tracheal intubation during general anesthesia, resulting in intraoperative hypotension. A thorough preoperative assessment and vigilant monitoring perioperatively ensure successful anesthesia management.

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Acupuncture-related interventions improve chemotherapy-induced peripheral neuropathy: A systematic review and network meta-analysis

• Mei-Ling Yeh 1 ,
• Ru-Wen Liao 2 ,
• Pin-Hsuan Yeh 1 ,
• Chuan-Ju Lin 3   na1 &
• Yu-Jen Wang 4   na1  

BMC Complementary Medicine and Therapies volume  24 , Article number:  310 ( 2024 ) Cite this article

Metrics details

The previous effects of acupuncture-related interventions in improving chemotherapy-induced peripheral neuropathy (CIPN) symptoms and quality of life (QoL) remain unclear in terms of pairwise comparisons.

This systematic review and network meta-analysis aimed to determine the hierarchical effects of acupuncture-related interventions on symptoms, pain, and QoL associated with CIPN in cancer patients undergoing chemotherapy.

Nine electronic databases were searched, including PubMed, Embase, Cochrane Library, EBSCO, Medline Ovid, Airiti Library, China National Knowledge Infrastructure (CNKI), China Journal full-text database (CJFD), and Wanfang. Medical subject heading terms and text words were used to search for eligible randomized controlled trials published from database inception to May 2023.

A total of 33 studies involving 2,027 participants were included. Pairwise meta-analysis revealed that acupuncture-related interventions were superior to usual care, medication, or dietary supplements in improving CIPN symptoms, CIPN pain, and QoL. Furthermore, network meta-analysis indicated that acupuncture plus electrical stimulation (acupuncture-E) had the greatest overall effect among the various interventions. The surface under the cumulative ranking curve (SUCRA) revealed that acupuncture-E ranked the highest in improving CINP symptoms. Acupuncture alone was most effective in reducing CIPN pain, and acupuncture plus moxibustion (acupuncture-M) ranked highest in enhancing QoL.

This finding suggests that acupuncture-related interventions can provide patients with benefits in improving CIPN symptoms, pain, and QoL. In particular, acupuncture-E could be the most effective approach in which the provided evidence offers diverse options for cancer patients and healthcare professionals.

Implication for the profession and/or patient care

These findings provide valuable insights into the potential benefits of acupuncture-related interventions for managing symptoms, pain, and QoL associated with CIPN in patients undergoing chemotherapy. Among the various interventions studied, overall, acupuncture-E had the most significant impact and was effective for a minimum duration of 3 weeks. On the other hand, transcutaneous electrical acupoint/nerve stimulation (TEAS) was identified as a noninvasive and feasible alternative for patients who had concerns about needles or the risk of bleeding. It is recommended that TEAS interventions should be carried out for a longer period, preferably lasting 4 weeks, to achieve optimal outcomes.

Trial registration

The study protocol was registered in the International Prospective Register of Systematic Reviews. Registration Number: CRD42022319871.

Peer Review reports

Introduction

According to cancer treatment guidelines, radical surgery is the main cancer treatment, while chemotherapy and concurrent chemoradiotherapy are used as adjuvant treatments [ 1 ]. Chemotherapy, which involves the use of cytotoxic chemicals to eliminate or shrink tumors, enhances survival rates [ 2 ]. However, chemotherapy-induced peripheral neuropathy (CIPN) has a high global prevalence rate of 85% [ 3 ], and 63% in Taiwan [ 4 ]. After chemotherapy, patients may persistently suffer from CIPN for several months to years or even experience irreversible sequelae [ 5 ]. The clinical characteristics of CIPN include paresthesia (tingling, burning sensation), hyperalgesia (sensitivity to noxious stimulation), allodynia (pain induced by normal innocuous stimulation), and decreased physical activity [ 5 , 6 ]. This may cause patients to receive reduced doses with decreased treatment efficacy or withdraw from chemotherapy. Notably, the severity of CIPN symptoms depends on drugs, doses, treatment period, and other comorbidities, such as diabetes, prior exposure to neurotoxic agents, and alcohol exposure [ 7 ]. While CIPN does not cause death directly, it causes important distress in the daily life of patients due to sensory and motor disorders and lowers their quality of life (QoL) [ 8 , 9 ].

Cytostatic groups of antineoplastic agents, especially those containing platinum, taxanes, and vinca alkaloids, induce CIPN through different mechanisms of neurotoxicity, but these remain unclear [ 6 , 10 ]. Platinum accumulates in the sensory nerve cell bodies and damages the DNA of the dorsal root ganglia, whereas taxane and vincristine inhibit the production of tubulin proteins and damage myelin surrounding neuronal axons, leading to the disruption of axonal transport [ 11 ]. CIPN occurs when neurotoxic antineoplastic drugs accumulate and lead to conduction dysfunction in the peripheral nervous system. CIPN symptoms have a common stocking-and-glove distribution, characterized by paranesthesia, dysesthesia, numbness, and tingling of feet and hands, which are associated with neuropathic pain [ 6 ]. At the onset of CIPN symptoms, chemotherapy is frequently decreased or stopped, with a possible deleterious impact on the oncological prognosis. Currently, there is no recommended agent for preventing CIPN, according to the American Society of Clinical Oncology [ 6 ]. As for treating CIPN, available data only point to duloxetine with moderate recommendation, but there is a lack of convincing evidence [ 12 ].

Systematic review studies have shown show that cancer patients seek additional help for CIPN, with 25–80% of them using non-pharmacological therapy [ 13 , 14 ]. Several systematic reviews have defined the benefits of reducing CIPN provided by acupuncture, massage, exercise, and dietary supplements [ 5 ]. Acupuncture-related interventions, which have drawn researchers’ attention in recent years, are widely accepted for their ancestral medical culture in the Chinese population and for their safety [ 15 ]. Acupuncture is an ancient practice that originated within traditional Chinese medicine, in which needles are inserted into the skin at acupoints throughout the body [ 16 ]. According to the principles of traditional Chinese medicine, stimulating acupoints leads to increased blood flow in the capillaries around the needle insertion sites, releases local opioid peptides, alters sympathetic tone, reduces inflammation, and stimulates specific areas of the brain [ 17 ]. Several systematic review studies have concluded that CIPN symptoms and pain can be improved by acupuncture [ 18 , 19 ] and acupuncture combined with electrical stimulation [ 20 , 21 ]. However, other studies did not support the improvement of symptoms by acupuncture [ 22 , 23 ]. In addition to symptom management, the importance of evidence-based practice is emphasized for improving QoL in patients with cancer. However, several studies have reported that acupuncture affects QoL [ 18 , 21 ], while others found no effect [ 19 ]. The above studies indicate that the effects of acupuncture-related interventions in improving neuropathy-related symptoms and QoL remain unclear in terms of pairwise comparisons. Therefore, this study systematically reviewed published studies and applied pairwise and network meta-analyses to determine not only the effects but also the hierarchy of acupuncture-related interventions on symptoms, pain, and QoL associated with CIPN in cancer patients undergoing chemotherapy.

Data sources and searches

A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) were conducted. This study’s report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The study protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022319871). Nine electronic databases were searched, including PubMed, Embase, Cochrane Library, EBSCO, Medline Ovid, Airiti Library, China National Knowledge Infrastructure (CNKI), China Journal full-text database (CJFD), and Wanfang. Medical subject heading (MeSH) terms and text words were used in the search strategy for searching eligible RCTs published from database inception to May 2023. Duplicate studies were removed. When similar studies by the same authors were found, the latest publication or that with high-quality evidence was chosen. Titles and abstracts were screened based on the selection criteria. Subsequently, the full texts of the studies were further reviewed for inclusion in the systematic review, and only complete data were included in the meta-analysis. A form collecting information on participants, intervention, comparison, and outcome (PICO) was used to compose key research questions. Cancer patients (P) were treated with acupuncture-related interventions (I) compared with usual care, medication, or dietary supplements (C) to determine the effects of acupuncture-related interventions on CIPN symptoms, CIPN pain, and QoL (O).

Inclusion and/or exclusion criteria

Participant types.

All RCTs used acupuncture techniques to manage CIPN problems, with no limitation on cancer types, sex, or race of adult patients diagnosed with CIPN. Individuals with peripheral neuropathic symptoms due to other factors such as diabetes mellitus, genetic disease, spinal cord injury, tumor compression, nutritional disorders, and alcoholism were excluded.

Intervention types

In general, acupuncture-related interventions involve various techniques for stimulating acupoints [ 24 ]. This study categorized acupuncture-related interventions into acupuncture alone, acupuncture plus electrical stimulation (Acupuncture-E), acupuncture plus moxibustion (Acupuncture-M), and transcutaneous electrical acupoint/nerve stimulation (TEAS).

Comparison types

The comparators used were usual care, medication, and dietary supplements. Usual care was defined as the chemotherapy protocol. The medication referred to medical drugs prescribed for CIPN. Dietary supplements were products with vitamin B taken orally.

Data extraction

The five research team members jointly obtained information from the included studies. Doubts and discrepancies were resolved through discussions. The accuracy of all the included studies was evaluated by the research team.

Assessment of methodological quality of included studies

Each RCT was independently assessed by the same research team. The Cochrane Collaboration’s Assessing Risk of Bias 2.0 tool was used, consisting of six domains: bias risk arising from the randomization process; bias risk due to deviations from the intended interventions; risk of missing outcome data; bias risk in measuring the outcomes; bias risk in selecting the reported results; and overall risk of bias [ 25 ]. Disagreements were resolved through discussion.

Data analysis

Statistical analyses were performed using the Cochrane Review Manager 5.4, CINeMA web application, and STATA version 15 statistical software. Pairwise and network meta-analyses using a random-effects model to pool each treatment was performed to compare the effects of the acupuncture-related interventions and the corresponding control group on the incidence rate of CIPN (risk ratio [RR]), the severity of CIPN pain (mean difference [MD]), and the level of QoL (standardized mean difference [SMD]). CINeMA was also used to perform an NMA through direct and indirect comparisons of the intervention effects. Finally, the surface under the cumulative ranking curve (SUCRA) was generated to determine the intervention hierarchy indicating the percentage of cumulative probability for each intervention to rank best [ 26 ].

Additionally, publication bias was qualitatively examined using Egger’s test. Certainty of evidence was evaluated using CINeMA grading the six domains: within-study bias, referring to the impact of risk of bias in the included studies; reporting bias, referring to publication and other reporting bias; indirectness; imprecision; heterogeneity; and incoherence. Results across domains were summarized together with the certainty of evidence according to four levels: very low, low, moderate, and high confidence. To assess the differences between direct and indirect comparisons and investigate the presence of a loop among the interventions, the consistency test using the χ 2 test for node-splitting analysis was used. A p  < 0.05 was considered statistically significant, and the 95% confidence interval (CI) was used.

Figure  1 shows the PRISMA flow diagram of the study selection process. There 2935 studies were identified using the electronic databases and 9 studies of grey literature obtained from other searching. Eventually, 33 and 31 studies were included in the meta-synthesis and meta-analysis, respectively. The characteristics of the included studies on acupuncture-related interventions were reported, involving 2027 patients suffering with CIPN (Table  1 ) [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. The average dropout rate of participants was 4.1%, with 4 RCTs reporting a rate between 13.7% [ 27 , 28 ] and 17.5% [ 40 , 54 ]. The age of participants averaged 57.99 years and was similar in the experimental and control groups. The targeted cancer types were colorectal cancer in 23 RCTs, breast cancer in 14 RCTs, lung cancer in 11 RCTs, gastric cancer in 14 RCTs, other cancers in 15 RCTs, and non-reported cancer type in 6 RCTs. Six RCTs studied cancer in stages II and III, 5 RCTs studied cancer in stages IV, 3 RCTs studied cancer in stage I, and 26 RCTs were not reported. The duration of interventions ranged between 2 and 16 weeks, with the majority being 3 weeks (10 RCTs), followed by 2 and 8 weeks (6 RCTs for each duration).

PRISMA flow diagram for systematic review of acupuncture-related treatments. Note, CNKI: China National Knowledge Infrastructure; CJFD: China Journal full-text database

Figure  2 illustrates the overall risk of bias assessment results, indicating that 35% of RCTs were classified as having a low risk of bias, while 45% were classified as having a high risk of bias. The primary concern was related to blinding. Consequently, a subgroup analysis was conducted to evaluate the clarity of the blinding process in these RCTs. Included studies were categorized into a "yes-blind" group if the blinding process was explicitly described and an "unclear-blind" group if it was not. Figures  3 , 4 , and 5 illustrate the impact of acupuncture-related treatments on CIPN symptoms, pain, and QoL, respectively. The subgroup analysis revealed significant effects on CIPN symptoms ( p  < 0.001) and pain ( p  < 0.001). However, the effect on CIPN QoL was significant only in the unclear-blind group ( p  < 0.001), and not in the yes-blind group ( p  = 0.35). Additionally, there were no significant differences between the two groups on CIPN symptoms ( p  = 0.77), pain ( p  = 0.62), and QoL ( p  = 0.91).

The results of the assessment of risk of bias

The effect of acupuncture-related interventions on CIPN symptoms improved by blinding classification

The effect of acupuncture-related interventions on CIPN pain reduced by blinding classification

The effect of acupuncture-related interventions on CIPN QoL improved by blinding classification

The degree of confidence in the evidence was obtained using the CINeMA (Appendices 1–3). All included studies were considered with no concerns about reporting bias and incoherence and some concerns about indirectness. The majority of comparisons were graded as moderate to low in CIPN pain and QoL but very low in CIPN symptoms. Additionally, the results from the loop inconsistency models for transitivity were obtained using the STATA (Appendices 4–6). These findings suggested that, overall, there was no substantial inconsistency in the comparisons made within the loop inconsistency models for CIPN symptoms, pain, and QoL. However, out of 13 loops, three exhibited significant inconsistency in CIPN QoL, specifically in comparing TENS and usual care, TENS and supplement, and acupuncture-M and supplement.

Effects of acupuncture-related interventions

Pairwise meta-analysis showed acupuncture-related interventions reduced the incidence of CIPN symptoms, with a significant difference compared to the control group (OR = 4.32, 95% CI = 3.09 to 6.02). Publication bias was not observed in the pooled studies (Egger’s test, p  = 0.32). A network plot of the included comparisons is shown in Fig.  6 . Table 2  shows the league table that acupuncture-E (OR = 16.56, 95% CI = 4.90 to 55.99; OR = 9.89, 95% CI = 4.18 to 23.40; OR = 15.99, 95% CI = 4.43 to 57.67) and acupuncture-M (OR = 5.16, 95% CI = 1.17 to 22.87; OR = 3.08, 95% CI = 1.11 to 8.57; OR = 4.98, 95% CI = 1.03 to 24.10) were significantly more effective than usual care, medication, and dietary supplements, respectively. Acupuncture (OR = 3.70; 95% CI, 1.50 to 9.12; OR = 3.57, 95% CI = 1.45 to 8.80) were significantly more effective than usual care, and dietary supplements, respectively. Additionally, TEAS was significantly more effective than usual care (OR = 5.77; 95% CI, 1.84 to 18.13). As determined by SUCRA and shown in Fig.  7 , acupuncture-E (87.8%) had the highest possibility of being the best intervention on CIPN symptoms.

Network plot for the outcomes of chemotherapy-induced peripheral neuropathy (CIPN) symptoms, pain, and quality of life. Note, the size of the nodes corresponds to the number of participants assigned to each treatment; treatments with direct comparisons are linked with a line; its thickness corresponds to the number of trials evaluating the comparison

Surface under the cumulative ranking curves for chemotherapy-induced peripheral neuropathy (CIPN) symptoms, CIPN pain, and quality of life

A pairwise meta-analysis of acupuncture-related interventions for alleviating CIPN pain showed a significant difference compared to the control group (MD = -1.05, 95% CI = -1.44 to -0.67). Publication bias was not observed in the pooled studies (Egger’s test, p  = 0.45). As shown in Table  2 , acupuncture (MD = -1.18, 95% CI = -2.23 to -0.12; MD = -1.28, 95% CI = -2.34 to -0.21) and acupuncture-E (MD = -1.12, 95% CI = -2.36 to -0.12; MD = -1.22, 95% CI = -2.42 to -0.01) were significantly more effective than usual care and dietary supplements, respectively. Acupuncture (MD = -1.18, 95% CI = -2.29 to -0.07) was significantly more effective than medication. SUCRA ranking revealed acupuncture (47.8%) had the highest likelihood of ranking highest (Fig.  7 ).

A pairwise meta-analysis of acupuncture-related interventions for improving QoL showed a significant difference (SMD = 0.51, 95% CI = 0.18 to 0.83). Publication bias was not observed in the pooled studies (Egger’s test, p  = 0. 44). As shown in Table  2 , acupuncture-E (SMD = 1.18, 95% CI = 0.27 to 2.09) was significantly more effective than usual care, acupuncture-E (SMD = 1.65, 95% CI = 0.52 to 2.77), acupuncture-M (SMD = 1.49, 95% CI = 0.43 to 2.55) and acupuncture (SMD = 1.12, 95% CI = 0.08 to 2.16) were significantly more effective than medication. SUCRA ranking revealed acupuncture-M (43.2%) had the highest likelihood of ranking highest (Fig.  7 ).

Safety of acupuncture-related interventions

Of the 33 RCTs, 14 reported information about adverse events. Minor dizziness, slight ecchymosis, nominal bleeding, swelling, and bruising at acupuncture sites have been reported [ 27 , 28 , 29 , 40 , 45 ]. As local hematomas developed, cold compresses were provided and the patient recovered within a few days. Seven RCTs reported no adverse events.

The evidence from this study supports the benefits of improving symptoms, pain, and QoL associated with CIPN by using acupuncture-related interventions. These interventions involved a variety of techniques including the use of needles, electrical stimulation, and moxibustion. Overall, acupuncture-E was the most effective among these interventions. Acupuncture alone could be the most effective intervention in decreasing CIPN pain; whereas acupuncture-M might be most effective for improving QoL. TEAS emerged as the second most effective intervention for alleviating CIPN symptoms, following acupuncture-E, which ranked first.

In CIPN patients, the immunological processes and production of neuroinflammation are impaired, leading to conduction dysfunctions in their peripheral nervous system [ 10 ]. CIPN refers to symptoms involving paranesthesia, dysesthesia, numbness, tingling, and neuropathic pain [ 6 , 11 ]. Through the stimulation of specific acupoints, acupuncture leads to the activation of sensory nerve endings and specific nerve fibers with transmission to the brain through nervous pathways. This process results in anti-neuroinflammatory effects on modulation [ 60 , 61 ] and nerve conduction [ 62 ], and stabilizes the concentration of ions inside and outside cells to avoid protein denaturation [ 63 ], which prevents and treats neurotoxicity. Pain-related problems are also improved by the release of endorphin, which is secreted from the pituitary gland, into the cerebral spinal fluid and blood to achieve an analgesic effect [ 64 ]. Acupuncture-induced analgesia may be mediated by the peripheral afferent Aβ, Aδ, and C nerve fibers. The gate control theory of pain confirms that after stimulation, the large myelinated Aβ fibers are excited by γ-aminobutyric acid interneurons in the spinal cord [ 65 ]. Stimuli through acupuncture at specific acupuncture points blocks the pain conduction of the Aδ and C fibers [ 65 ].

Similarly to acupuncture, an electric stimulus delivered to acupuncture points activates nerve fibers and produces analgesic effects [ 66 ]. A systematic review pointed out that acupuncture-E effectively decreased CIPN pain compared to Vitamin B [ 21 ]. One key advantage of electrical stimulation is the enhancement of analgesic action through a consistent and adjustable electric current and power [ 64 ]. Acupuncture-E effectively reduced CIPN symptoms in a study in which they improved motor and sensory disorders, especially by contributing to increased sensory nerve conduction velocity [ 20 , 21 ]. As the nerve conduction velocity in the limbs increased, their functional status improved. This study also supports that the overall effect acupuncture-E and TEAS for managing CIPN symptoms and pain is superior to that of usual care, medication and vitamin B supplements.

In the included studies, there were reports of not major adverse events associated with acupuncture, such as slight ecchymosis, nominal bleeding, swelling, and bruising at the site of acupuncture. However, it is important to note that these adverse events did not occur when using TEAS, a non-invasive technique. For patients with cancer who have platelet dysfunction, TEAS can be considered as an alternative to acupuncture for improving symptoms and pain related to CIPN. This substitution is beneficial because it helps to avoid the risk of bleeding tendencies associated with acupuncture. Although TEAS may require a longer course of intervention to effectively reduce CIPN symptoms, particularly in cases of neuropathic, intermittent, and continuous pain [ 67 ], it offers several mechanisms that contribute to its effect. TEAS may improve CIPN symptoms is by reducing excitability and enhancing inhibition of the central nervous system. CIPN symptoms are partially attributed to increased excitability and decreased inhibition, and TEAS has been shown to address these factors [ 11 ]. Furthermore, evidence suggests that TEAS activates opioid receptors, which play a role in pain inhibition [ 68 , 69 ]. Electrical stimulation through TEAS also triggers the release of neuroactive substances and inhibits glial cell activation in the peripheral nervous system, contributing to its analgesic effects [ 61 ]. The analgesic effects of TEAS have been observed in patients with diabetic peripheral neuropathy [ 70 ]. Additionally, a systematic review confirmed that TEAS has a positive effect on motor nerve conduction velocity and improves diabetic peripheral neuropathy [ 71 ].

Acupuncture-related interventions, particularly acupuncture-M, demonstrated the potential to improve QoL in this study. Moxibustion, which involves applying a heat source to acupoints, may provide local somatothermal stimulation and affect oxidative stress in the viscera [ 72 ]. However, inconsistencies were observed between direct and indirect comparisons of the intervention effects on QoL, leading to variations in the results of this study. Although these inconsistencies did not alter the overall findings, they did lower the evidence level. The absence of direct comparisons between acupuncture-M and supplements may contribute to discrepancies arising from the transitivity of indirect comparisons [ 73 ]. Additionally, the reliance on subjective measurements through questionnaires and the small number of studies included in the loop [ 74 ], and the use of various control groups [ 73 ] may also lead to inconsistencies between direct and indirect. Measuring QoL is inherently complex and requires careful consideration. A significant challenge in network meta-analysis is managing the inconsistency between direct and indirect evidence for acupuncture-M comparisons.

Additionally, the impact of acupuncture-related interventions on CIPN symptoms and pain in this study was not influenced by the presence or absence of blinding procedures. However, in the yes-blind group, non-significant effects on CIPN QoL, which may be attributed to the small sample size. Blinding patients and researchers to interventions is challenging due to the nature of acupuncture-related interventions. A previous study indicated that there was no significant difference in intervention effects between trials with and without blinded participants, healthcare providers, or outcome assessors [ 75 ]. Conversely, another study found that intervention effects were overestimated in unblinded trials [ 76 ]. Adhering to evidence-based standards is crucial to minimizing the risk of bias and improving the quality of evidence in future RCTs.

This study has several limitations. First, blinding of participants and researchers in the included studies was either not reported or not performed, which somehow led to within-study bias. Due to the nature of acupuncture, the stimulation of acupoints with needles or electricity is always perceived by patients and known to practitioners. This study suggests employing blinding procedures whenever possible. If the outcome evaluators were blinded, measurement bias would be minimized. Similarly, if the statistical analysts were blinded, detection bias would be minimized. Second, direct and indirect comparisons of data from multiple studies may result in some inconsistencies, limiting the robustness and precision of the results. While this issue did not affect the network meta-analysis results, it did decrease the evidence level. It is also important to note the insufficient number of studies, which could impact the transitivity of indirect comparisons. Last, only published Chinese and English studies were included, which may have led to language bias.

Conclusions

In clinical practice, although interruption or reduction in the dose of chemotherapy is the recommended treatment for CIPN, such approach hampers the effect of chemotherapeutic agents on tumor growth control. However, these patients suffering from CIPN represents a significant burden on physical health and daily life. This systematic review and network meta-analysis provides clinical professionals and patients with scientific evidence and a range of options based on the hierarchical effects of acupuncture-related interventions. This study confirmed the benefits of acupuncture-related interventions, especially acupuncture-E, in improving symptoms, pain and QoL associated with CIPN for patients undergoing chemotherapy. Acupuncture-E had the most significant impact and was effective for a minimum duration of 3 weeks. Additionally, TEAS was identified as a noninvasive and feasible alternative for patients who had concerns about needles or the risk of bleeding. However, it is recommended that TEAS should be carried out for a longer period, preferably lasting 4 weeks, in order to achieve optimal outcomes. Acupuncture-M was the most effective approach in improving QoL. Few included studies reported adverse events but the relative safety of acupuncture-related interventions requires further study. Overall, acupuncture-related interventions had few complications and demonstrated high safety and accessibility, improving CIPN symptoms, pain and QoL in patients. Large-sample, randomized controlled trials are warranted to investigate CIPN caused by different chemotherapeutics, cancer types and staging to clarify the advantages of acupuncture-related interventions.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Acupuncture plus electrical stimulation

Acupuncture plus moxibustion

• Chemotherapy-induced peripheral neuropathy

Network meta-analysis

Participants, intervention, comparison, and outcome

• Quality of life

Randomized controlled trials

Transcutaneous electrical acupoint/nerve stimulation

National Comprehensive Cancer Network. NCCN guidelines: colon cancer. 2021. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428 . Accessed 20 May 2021.

Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–85. https://doi.org/10.3322/caac.21565 .

Article   PubMed   Google Scholar  

Zajaczkowska R, Kocot-Kepska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of chemotherapy-induced neuropathy. Int J Mol Sci. 2019;20(6):1451. https://doi.org/10.3390/ijms20061451 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Wang YJ, Chan YN, Jheng YW, Wu CJ, Lin MW, Tseng LM, et al. Chemotherapy-induced peripheral neuropathy in newly diagnosed breast cancer survivors treated with taxane: a prospective longitudinal study. Support Care Cancer. 2021;29(6):2959–71. https://doi.org/10.1007/s00520-020-05796-0 .

Brami C, Bao T, Deng G. Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: a systematic review. Crit Rev Oncol Hematol. 2016;98:325–34. https://doi.org/10.1016/j.critrevonc.2015.11.014 .

Loprinzi CL, Lacchetti C, Bleeker J, Cavaletti C, Chauhan DL, Hertz MR, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020;38(28):3325–48. https://doi.org/10.1200/JCO.20.01399 .

Tzatha E, DeAngelis LM. Chemotherapy-induced peripheral neuropathy. Oncology (Williston Park). 2016;30(3):240–4.

PubMed   Google Scholar  

Bonhof CS, van de Poll-Franse LV, Wasowicz DK, Beerepoot LV, Vreugdenhil G, Mols F. The course of peripheral neuropathy and its association with health-related quality of life among colorectal cancer patients. J Cancer Surviv. 2021;15(2):190–200. https://doi.org/10.1007/s11764-020-00923-6 .

Prieto-Callejero B, Rivera F, Fagundo-Rivera J, Romero A, Romero-Martín M, Gómez-Salgado J, et al. Relationship between chemotherapy-induced adverse reactions and health-related quality of life in patients with breast cancer. Medicine. 2020;99(33): e21695. https://doi.org/10.1097/MD.0000000000021695 .

Article   PubMed   PubMed Central   Google Scholar  

Makker PG, Duffy SS, Lees JG, Perera CJ, Tonkin RS, Butovsky O, et al. Characterisation of immune and neuroinflammatory changes associated with chemotherapy-induced peripheral neuropathy. PLoS ONE. 2017;12(1): e0170814. https://doi.org/10.1371/journal.pone.0170814 .

Kandula T, Farrar MA, Kiernan MC, Krishnan AV, Goldstein D, Horvath L, et al. Neurophysiological and clinical outcomes in chemotherapy-induced neuropathy in cancer. Clin Neurophysiol. 2017;128(7):1166–75. https://doi.org/10.1016/j.clinph.2017.04.009 .

Velasco R, Besora S, Argyriou AA, Santos C, Sala R, Izquierdo C, et al. Duloxetine against symptomatic chemotherapy-induced peripheral neurotoxicity in cancer survivors: a real world, open-label experience. Anticancer Drugs. 2021;32(1):88–94. https://doi.org/10.1097/CAD.0000000000001005 .

Article   CAS   PubMed   Google Scholar  

Alsharif F. Discovering the use of complementary and alternative medicine in oncology patients: a systematic literature review. Evid Based Complement Alternat Med. 2021;2021:6619243. https://doi.org/10.1155/2021/6619243 .

Samuels N, Ben-Arye E. Integrative approaches to chemotherapy-induced peripheral neuropathy. Curr Oncol Rep. 2020;22(3):23. https://doi.org/10.1007/s11912-020-0891-2 .

Baviera AF, Olson K, Paula JM, Toneti BF, Sawada NO. Acupuncture in adults with chemotherapy-induced peripheral neuropathy: a systematic review. Rev Lat Am Enfermagem. 2019;27: e3126. https://doi.org/10.1590/1518-8345.2959.3126 .

Zhu H. Acupoints initiate the healing process. Med Acupunct. 2014;26(5):264–70. https://doi.org/10.1089/acu.2014.1057 .

Yeh ML, Lin KC, Chen HH, Wang YJ, Huang YC. Use of traditional medicine and complementary and alternative medicine in Taiwan: a multilevel analysis. Holist Nurs Pract. 2015;29(2):87–95. https://doi.org/10.1097/HNP.0000000000000071 .

Chien TJ, Liu CY, Fang CJ, Kuo CY. The efficacy of acupuncture in chemotherapy-induced peripheral neuropathy: systematic review and meta-analysis. Integr Cancer Ther. 2019;18:1534735419886662. https://doi.org/10.1177/1534735419886662 .

Oh PJ, Kim YL. Effectiveness of non-pharmacologic interventions in chemotherapy induced peripheral neuropathy: a systematic review and meta-analysis. J Korean Acad Nurs. 2018;48(2):123–42. https://doi.org/10.4040/jkan.2018.48.2.123 .

Hwang MS, Lee HY, Choi TY, Lee JH, Ko YS, Jo DC, et al. A systematic review and meta-analysis of the efficacy of acupuncture and electro-acupuncture against chemotherapy-induced peripheral neuropathy. Medicine. 2020;99(17): e19837. https://doi.org/10.1097/MD.0000000000019837 .

Kuang B, Li M, Zeng H, MO A. Meta-analysis of electroacupuncture for chemotherapy-induced peripheral neuropathy. Tianjin J Tradit Chin Med. 2019;(7):673–8. https://doi.org/10.11656/j.issn.1672-1519.2019.07.13 .

Hao J, Zhu X, Bensoussan A. Effects of nonpharmacological interventions in chemotherapy-induced peripheral neuropathy: an overview of systematic reviews and meta-analyses. Integr Cancer Ther. 2020;19:1534735420945027. https://doi.org/10.1177/1534735420945027 .

Jin Y, Wang Y, Zhang J, Xiao X, Zhang Q. Efficacy and safety of acupuncture against chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2020;2020:8875433. https://doi.org/10.1155/2020/8875433 .

Yeh ML, Hsu CC, Chen CH. Traditional Chinese medicine in nursing care. 3rd ed. Taiwan: Wunan; 2020.

Higgins JPT, Sterne JAC, Savović J, Page MJ, Hróbjartsson A, Boutron I, et al. A revised tool for assessing risk of bias in randomized trials. Cochrane Database Syst Rev. 2016;10(Supp 1):29–31.

Google Scholar  

Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71. https://doi.org/10.1016/j.jclinepi.2010.03.016 .

Bao T, Patil S, Chen C, Zhi IW, Li QS, Piulson L, et al. Effect of acupuncture vs sham procedure on chemotherapy-induced peripheral neuropathy symptoms: a randomized clinical trial. JAMA Netw Open. 2020;3(3): e200681. https://doi.org/10.1001/jamanetworkopen.2020.0681 .

Bao T, Baser R, Chen C, Weitzman M, Zhang YL, Seluzicki C, et al. Health-related quality of life in cancer survivors with chemotherapy-induced peripheral neuropathy: a randomized clinical trial. Oncologist. 2021;26(11):e2070–8. https://doi.org/10.1002/onco.13933 .

Cao SC, Zhong Y, Zhang HS, Zhang SQ, Zhuang HW, Wang ZM, et al. Electroacupuncture reduces peripheral neurotoxicity and improves quality of life in cancer patients with Vinca alkaloids chemotherapy. J Pract Oncol. 2015;30(4):374–7. https://doi.org/10.13267/j.cnki.syzlzz.2015.04.046 .

Chang WW. Clinical trial of electroacupuncture stimulation on prevention and treatment of oxaliplatin neurotoxicity (Master Dissertation). China’s mainland: Dalian University of Traditional Chinese Medicine; 2018.

Cui DL, Wang LX, Fu CJ. Clinical observation of moxibustion-acupuncture and in the treatment of oxaliplatin neurotoxicity. Gansu J Tradit Chin Med. 2011;24(2):45–6.

Dai LJ, Xu BG, Wang J. Effect of needle warming moxibustion on cancer chemotherapy-induced toxicity and side effect. Hebei J Tradit Chin Med. 2011;33(8):1191–2, 1195.

Han X, Wang L, Shi H, Zheng G, He J, Wu W, et al. Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma. BMC Cancer. 2017;17(1):40. https://doi.org/10.1186/s12885-016-3037-z .

Hou HK, Cheng HY. Effect of acupuncture on chemotherapy-related peripheral neurotoxicity and digestive tract adverse effects of malignant tumor patients: a clinical study on 20 cases. J Tradit Chin Med. 2011;52(23):2031–3. https://doi.org/10.13288/j.11-2166/r.2011.23.015 .

Iravani S, Kazmi Motlagh AH, Emami Razavi SZ, Shahi F, Wang J, Hou L, et al. Effectiveness of acupuncture treatment on chemotherapy-induced peripheral neuropathy: a pilot, randomized, assessor-blinded, controlled trial. Pain Res Manag. 2020;2020:2504674. https://doi.org/10.1155/2020/2504674 .

Kong FH. Clinical observation of electro-acupuncture combined with chemotherapy for the prevention and treatment of peripheral neurotoxicity caused by docetaxel [Conference presentation]. 2nd annual conference of acupuncture and rehabilitation branch of the Chinese association for the promotion of traditional Chinese medicine and the 9th annual meeting of the Shandong Acupuncture and Moxibustion Society, 3. 2017.

Li DQ, Luo JQ, Zhang H. Effect on the prevention and treatment of neurotoxicity of malignant tumor by electroacupuncture after chemotherapy. China J Chin Med. 2012;27(8):928–30. https://doi.org/10.16368/j.issn.1674-8999.2012.08.006 .

Lin JY. Clinical observation on the effect of improved treatment of acupuncture on treating CIPN with Qi deficiency and blood stasis (Master Dissertation). China’s mainland: Fujian University of Traditional Chinese Medicine; 2019.

Lou B, Zhang LW, Xu K, Luo HY, Li Y. Clinical observation on acupuncture treatment of peripheral nervous system toxicity induced by chemotherapy drugs. Hebei J Tradit Chin Med. 2009;31(7):1040–1.

Lu W, Giobbie-Hurder A, Freedman RA, Shin IH, Lin NU, Partridge AH, et al. Acupuncture for chemotherapy-induced peripheral neuropathy in breast cancer survivors: a randomized controlled pilot trial. Oncologist. 2020;25(4):310–8. https://doi.org/10.1634/theoncologist.2019-0489 .

Molassiotis A, Suen LKP, Cheng HL, Mok TSK, Lee SCY, Wang CH, et al. A randomized assessor-blinded wait-list-controlled trial to assess the effectiveness of acupuncture in the management of chemotherapy-induced peripheral neuropathy. Integr Cancer Ther. 2019;18:1534735419836501. https://doi.org/10.1177/1534735419836501 .

Pan XJ, Gu F, Huang LH, Li YM. Clinical study on transcutaneous electrical acupuncture for prevention of peripheral neuritis in patients with lung cancer undergoing chemotherapy. Chin Nurs Res. 2018;32(20):3274–7. https://doi.org/10.12102/j.issn.1009-6493.2018.20.029 .

Rostock M, Jaroslawski K, Guethlin C, Ludtke R, Schröder S, Bartsch HH, et al. Chemotherapy-induced peripheral neuropathy in cancer patients: a four-arm randomized trial on the effectiveness of electroacupuncture. Evid Based Complement Alternat Med. 2013;2013: 349653. https://doi.org/10.1155/2013/349653 .

Stringer J, Ryder WD, Mackereth PA, Misra V, Wardley AM. A randomised, pragmatic clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (ACUFOCIN). Eur J Oncol Nurs. 2022;60: 102171. https://doi.org/10.1016/j.ejon.2022.102171 .

Su ZJ. Clinical research of intradermal acupuncture for chemotherapy-induced peripheral neuropathy in patients with gastric cancer or colorectal cancer (Master Dissertation). China’s mainland: Shanghai University of Traditional Chinese Medicine; 2019.

Sui MH, Xu N, Xiang Y, Shu GJ, Jin DM, Yan TB. The influence of electrical acupuncture on the chemotherapy induced neuropathic pain and quality of life. Chin J Integr Med Cardio-/Cerebrovasc Dis. 2018;16(10):1331–3. https://doi.org/10.12102/j.issn.1672-1349.2018.10.06 .

Sun XJ, He SL, Chen H, Shen J, Wu WB, Liu LM, et al. Clinical study of electroacupuncture treatment for oxaliplatin neurotoxicity. Shanghai J Acupunct Moxibustion. 2012;31(10):727–9. https://doi.org/10.3969/j.issn.1005-0957.2012.10.727 .

Article   Google Scholar  

Tian YP, Zhang Y, Jia YJ. The curative effect of warm acupuncture and moxibustion on peripheral neurotoxicity caused by oxaliplatin. Tianjin J Tradit Chin Med. 2011;28(6):212–3.

Tian HZ. The clinical observation of curative effect acupuncture on chemotherapy-induced peripheral neuropathy caused by FOL-FOX4 regimen (Master Dissertation). China’s mainland: Heilongjiang University of Traditional Chinese Medicine; 2016.

Wang B. Clinical study of peripheral neuropathy caused by acupuncture in patients with colorectal cancer oxaliplatin chemotherapy (Master Dissertation). China’s mainland: Beijing University of Chinese Medicine; 2011.

Wang YH. Influence on the toxicity and side effects of malignant tumor chemotherapy with fire needle on sihua points (Master Dissertation). China’s mainland: Guangzhou University of Chinese Medicine; 2014.

Wang B. Clinical study on electroacupuncture combined with mecobalamin in the treatment of chemotherapy-induced peripheral neuropathy in multiple myeloma (Master Dissertation). China’s mainland: Gansu University of Chinese Medicine; 2018.

Wang L, Xu X, Yao L, Huang Y, Zou Q, Wu B, et al. Intervention effect of acupuncture and moxibustion in treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma. J Clin Med Pract. 2022;26(2):28–30. https://doi.org/10.7619/jcmp.20212712 .

Article   CAS   Google Scholar  

Wong R, Major P, Sagar S. Phase 2 study of acupuncture-like transcutaneous nerve stimulation for chemotherapy-Induced peripheral neuropathy. Integr Cancer Thera. 2016;15(2):153–64. https://doi.org/10.1177/1534735415627926 .

Wu Y, Zeng Y, Leng Y. Clinical observation of acupuncture prevention and cure effect on the nitrobenzene induced neurotoxicity in the circuit of chemotherapy period. Clin J Tradit Chin Med. 2018;30(4):725–8. https://doi.org/10.16448/j.cjtcm.2018.0219 .

Xiang Y, Xu N, Sui MH. Clinical observation on electroacupuncture in the treatment of chemotherapy-induced pathologic neuropathyic pain. Chin J Integr Med Cardio-/Cerebrovasc Dis. 2018;16(9):1168–71.

Xu WR, Hua BJ, Hou W, Bao YJ. Clinical randomized controlled study on acupuncture for treatment of peripheral neuropathy induced by chemotherapeutic drugs. Chin Acupunct Moxibustion. 2010;30(6):457–60. https://doi.org/10.13703/j.0255-2930.2010.06.011 .

Yan YJ, He CL, Dong CH. Clinical study on acupuncture for treatment of peripheral neuropathy induced by chemotherapeutic drugs. J Liaoning Univ Tradit Chin Med. 2012;14(8):232–3. https://doi.org/10.13194/j.jlunivtcm.2012.08.232.yanyj.075 .

Zhang S, Wu T, Zhang H, Yang Y, Jiang H, Cao S, et al. Effect of electroacupuncture on chemotherapy-induced peripheral neuropathy in patients with malignant tumor: a single-blinded, randomized controlled trial. J Tradit Chin Med. 2017;37(2):179–84. https://doi.org/10.1016/s0254-6272(17)30042-0 .

Dou B, Li Y, Ma J, Xu Z, Fan W, Tian L, et al. Role of neuroimmune crosstalk in mediating the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain. Front Neurosci. 2021;15: 695670. https://doi.org/10.3389/fnins.2021.695670 .

Li N, Guo Y, Gong Y, Zhang Y, Fan W, Yao K, et al. The anti-inflammatory actions and mechanisms of acupuncture from acupoint to target organs via neuro-immune regulation. J Inflamm Res. 2021;14:7191–224. https://doi.org/10.2147/JIR.S341581 .

Jiang K, Sun Y, Chen X. Mechanism underlying acupuncture therapy in spinal cord injury: a narrative overview of preclinical studies. Front Pharmacol. 2022;13: 875103. https://doi.org/10.3389/fphar.2022.875103 .

Liddle CE, Harris RE. Cellular reorganization plays a vital role in acupuncture an algesia. Med Acupunct. 2018;30(1):15–20. https://doi.org/10.1089/acu.2017.1258 .

Lv Q, Wu F, Gan X, Yang X, Zhou L, Chen J, et al. The involvement of descending pain inhibitory system in electroacupuncture-induced analgesia. Front Integr Neurosci. 2019;13:38. https://doi.org/10.3389/fnint.2019.00038 .

Lai HC, Lin YW, Hsieh CL. Acupuncture-analgesia-mediated alleviation of central sensitization. Evid Based Complement Alternat Med. 2019;2019:6173412. https://doi.org/10.1155/2019/6173412 .

Han QQ, Fu Y, Le JM, Ma YJ, Wei XD, Ji HL, et al. The therapeutic effects of acupuncture and electroacupuncture on cancer-related symptoms and side-effects. J Cancer. 2021;12(23):7003–9. https://doi.org/10.7150/jca.55803 .

Gewandter JS, Chaudari J, Ibegbu C, Kitt R, Serventi J, Burke J, et al. Wireless transcutaneous electrical nerve stimulation device for chemotherapy-induced peripheral neuropathy: an open-label feasibility study. Support Care Cancer. 2019;27(5):1765–74. https://doi.org/10.1007/s00520-018-4424-6 .

Bi Y, Wei Z, Kong Y, Hu L. Supraspinal neural mechanisms of the analgesic effect produced by transcutaneous electrical nerve stimulation. Brain Struct Funct. 2021;226(1):151–62. https://doi.org/10.1007/s00429-020-02173-9 .

Gozani SN. Remote analgesic effects of conventional transcutaneous electrical nerve stimulation: a scientific and clinical review with a focus on chronic pain. J Pain Res. 2019;12:3185–201. https://doi.org/10.2147/JPR.S226600 .

Serry ZMH, Mossa G, Elhabashy H, Elsayed S, Elhadidy R, Azmy RM, et al. Transcutaneous nerve stimulation versus aerobic exercise in diabetic neuropathy. Egypt J Neurol Psychiatr Neurosurg. 2016;53(2):124–9. https://doi.org/10.4103/1110-1083.183449 .

Zeng H, Pacheco-Barrios K, Cao Y, Li Y, Zhang J, Yang C, et al. Non-invasive neuromodulation effects on painful diabetic peripheral neuropathy: a systematic review and meta-analysis. Sci Rep. 2020;10(1):9184. https://doi.org/10.1038/s41598-020-75922-9 .

Chiu JH. How does moxibustion possibly work? Evid Based Complement Alternat Med. 2013;2013:198584. https://doi.org/10.1155/2013/198584 .

Veroniki AA, Vasiliadis HS, Higgins JP, Salanti G. Evaluation of inconsistency in networks of interventions. Int J Epidemiol. 2013;42(1):332-45. https://doi.org/10.1093/ije/dys222 .

Song F, Xiong T, Parekh-Bhurke S, Loke YK, Sutton AJ, Eastwood AJ, et al. Inconsistency between direct and indirect comparisons of competing interventions: meta-epidemiological study. BMJ. 2011;343:d4909. https://doi.org/10.1136/bmj.d4909 .

Moustgaard H, Clayton GL, Jones HE, Boutron I, Jørgensen L, Laursen DRT, et al. Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study. BMJ. 2020;368:l6802. https://doi.org/10.1136/bmj.l6802 .

Martin GL, Trioux T, Gaudry S, Tubach F, Hajage D, Dechartres A. Association between lack of blinding and mortality results in critical care randomized controlled trials: a meta-epidemiological study. Crit Care Med. 2021;49(10):1800-11. https://doi.org/10.1097/CCM.0000000000005065 .

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Department of Nursing, National Taipei University of Nursing and Health Sciences, No. 365, Minte Rd., Peitou Dist., Taipei City, 11219, Taiwan

Mei-Ling Yeh & Pin-Hsuan Yeh

Department of Nursing, Taipei Tzu Chi Hospital, No. 289, Jianguo Rd., Xindian Dist., New Taipei City, 23142, Taiwan

Ru-Wen Liao

Department of Nursing, Hsinchu Cathay General Hospital, No. 678, Sec. 2 Zhonghua Rd., East Dist., Hsinchu City, 300003, Taiwan

Chuan-Ju Lin

Department of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhwa 1 Rd., Guishan Dist., Taoyuan City, 333324, Taiwan

Yu-Jen Wang

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ML Yeh: Conceptualization, Methodology, Formal analysis, Data curation, Writing-original draft, Writing-review & editing, Supervision, Project administration. RW Liao: Conceptualization, Investigation. PH Yeh: Investigation, Data curation, Visualization, Writing-original draft. CJ Lin: Conceptualization, Methodology, Formal analysis, Data curation, Writing-original draft, Writing-review & editing, Visualization. YJ Wang: Methodology, Investigation, Data curation, Visualization, Writing-review & editing.

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Yeh, ML., Liao, RW., Yeh, PH. et al. Acupuncture-related interventions improve chemotherapy-induced peripheral neuropathy: A systematic review and network meta-analysis. BMC Complement Med Ther 24 , 310 (2024). https://doi.org/10.1186/s12906-024-04603-1

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Received : 01 September 2023

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DOI : https://doi.org/10.1186/s12906-024-04603-1

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A Review of Recent Pharmacological Advances in the Management of Diabetes-Associated Peripheral Neuropathy

1 Advocate Illinois Masonic Medical Center, Department of Anesthesiology, Chicago, IL 60657, USA; [email protected] (O.S.); moc.liamg@cicnajrp (P.J.)

2 Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA

Predrag Jancic

Nebojsa nick knezevic.

3 Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA

4 Department of Surgery, University of Illinois, Chicago, IL 60612, USA

Associated Data

Not applicable.

Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and economic burden, with patients requiring concomitant medication and often experiencing a decline in their quality of life. There is currently a wide variety of pharmacological interventions, including serotonin norepinephrine reuptake inhibitors, gapentanoids, sodium channel blockers, and tricyclic antidepressants. These medications will be discussed, as well as their respective efficacies. Recent advances in the treatment of diabetes mellitus with incretin system-modulating drugs, specifically glucagon-like peptide-1 agonists, have been promising, and their potential implication in the treatment of peripheral diabetic neuropathy is discussed in this review.

1. Introduction

Diabetic peripheral neuropathy (DPN) is defined as a disorder primarily associated with diabetes mellitus without any evident correlation to other causes of peripheral nerve damage [ 1 ]. The plethora of symptoms attributed to DPN is explained by the extensive amount of diabetic neuropathy (DN) forms, including polyneuropathy, mononeuropathy, radiculoplexopathy, autonomic neuropathy, and others [ 2 ]. However, an absence of symptoms does not exclude DN, as asymptomatic presentation is common [ 3 ]. Of the vast variety of presenting DN forms, distal sensorimotor polyneuropathy (DSMP) overshadows other entities, accounting for 75–90% of DPN cases [ 2 , 4 ].

The aim of this review paper is to highlight the current available knowledge of DPN pain and to shine a light on the direction in which clinical trials are headed with pharmacological treatment.

2. Clinical Characteristics

Clinical findings on DSMP can be roughly categorized into two groups, positive and negative. The hallmark of positive findings is pain, followed by allodynia (regular stimuli such as touch and pressure cause pain) and hyperalgesia (increased pain intensity to a stimulus that usually causes less pain) [ 5 ]. Of the patients with DSMP, up to 25% may experience pain as their main symptom [ 3 , 4 , 6 , 7 ].

Negative symptoms include decreased sensation to touch, temperature, and pain, which can result in ataxia and other motor disabilities [ 8 , 9 ].

Pain in diabetic patients can be categorized into non-neuropathic and neuropathic. Due to a complex array of factors included in the pathophysiology of diabetes, non-neuropathic pain can arise from different vascular, osteochondral, and neural structures (peripheral vascular disease, spinal stenosis, radiculopathy, etc.) [ 2 ]. Successfully distinguishing between these two types of pain is essential for diagnosing and treating neuropathic pain. Moreover, it is suggested that pain of neuropathic origin is greater in intensity and less likely to respond to medication compared to non-neuropathic pain [ 10 ].

Neuropathic pain presents symmetrically and distally, and is usually associated with burning, prickling, and shooting sensations. This clinical presentation is often a sign of small nerve fiber involvement [ 3 , 4 , 6 , 8 ]. Damage to larger nerves may give rise to predominantly negative symptoms (numb feet, loss of sensation), which puts patients at risk of further complications, such as feet deformities and ulcerations [ 11 ]. Large fiber damage can also present with ataxic gait and frequent falls [ 12 , 13 ].

3. Epidemiology

In the setting of urbanization and inadequate dietary trends, the prevalence of diabetes mellitus and its complications is on a steep incline [ 14 ]. Recent findings suggest that 8.5% of the world population has a diagnosis of diabetes, with that number expected to exponentially increase in the coming years [ 15 ]. A 2018 report shows that 23.4 million people in the US have diagnosed diabetes. Moreover, 81.6 million US citizens (33.9%) have prediabetes [ 16 ].

A concerning finding shows that 17.7% of US adolescents aged 12–19 have prediabetes, whereas 28.5% of those with diabetes are undiagnosed [ 16 ]. A staggering 22.9% of people with diabetes are undiagnosed and untreated in the US [ 16 ]. Taking these numbers into account, it is easily deduced that the incidence of diabetic complications is on the rise, and more focus should be placed on the prevention of such complications, rather than treatment [ 4 ].

Due to the varying degree of clinical presentation, lack of awareness of the disease progression, and an unclear standard in diagnostic protocols, the prevention and treatment of DPN is often challenging [ 3 , 17 , 18 , 19 ]. With these challenges in mind, making a concrete statement regarding the prevalence of diabetic complications is often difficult. This difficulty is in part due to the multifactorial pathogenesis of such complications. Studies have found that, besides glycemia, key players in neuropathy formation include hypertension, smoking, obesity, and elevated triglyceride levels [ 20 ].

The estimated prevalence of DSMP varies in the literature, but studies suggest that up to 15% of newly diagnosed cases of diabetes have concomitant DSMP, with that number rising up to 50% during the 10-year progression of the disease [ 4 , 21 ]. Certain papers estimate that 28% of diabetic patients in a primary care setting have DSMP, with this number being approximately 20% for the total diabetic population [ 7 , 22 ].

Among patients with type 1 diabetes, the prevalence of DSMP is somewhat misleading. One study showed that 8.2% of diagnosed youth had DSMP, whereas the prevalence in adolescents with type 2 diabetes paralleled that in the adult population (25.7%) [ 23 ]. However, other studies reported higher numbers for type 1 diabetes-associated DSMP, ranging from 23% [ 24 ] to 27% [ 25 ].

Concerning primarily type 1 diabetes, an association worth noting is between puberty and the onset of diabetic complications. Studies have suggested that the hormonal changes happening throughout puberty lead to a variety of pathophysiological processes that can result in a significant increase in incidence of diabetic complications [ 26 , 27 , 28 ].

4. Societal and Economic Burden

It is of no surprise that chronic pain leaves a trail through multiple facets of a person’s life, including mental health and well-being. A staggering statistic shows that 43% of patients with DSMP use concomitant medication (for anxiety, depression, sleep deprivation, etc.), illustrating the beginning of the humanitarian burden that this disease brings [ 29 ].

When scoring DSMP patients on a scale that represents the interference of pain in their everyday activities, there is a trend of higher scores, corresponding to an increased interference rate [ 30 ]. Moreover, scales testing for daily living disability, quality of sleep, and frequency of anxiety and depression among patients show the same trend [ 30 , 31 ].

Diabetic neuropathy and its complications contribute to an estimated 27% of total annual costs aimed at diabetes management [ 32 ]. Therefore, the economic burden of DSMP is two-fold. Not only is the cost of polypharmacy required for these patients considerable, but the productivity lost in a society due to these disabilities is substantial [ 31 ].

5. Pharmacological Management in Diabetic Peripheral Neuropathy

The management of DPN is a complicated subject with cultural and patient-specific nuances. For the purposes of this review article, the “standards of care” shall be drawn from the 2022 American Academy of Neurology’s (AAN) practice guidelines [ 33 ], as well as the 2023 American Diabetes Association (ADA) standards of care [ 34 ]. This review article will provide a brief synopsis of these medications as well as attempt to elucidate the usage of new medications in the treatment and prevention of DPN. Therefore, the two main categories of medications reviewed in this paper are symptomatic treatments, focusing on the treatment of pain in DPN (SNRIs, gabapentinoids, sodium channel blockers, and TCAs), and pathogenesis-based treatments (GLP-1 agonists). A summary of the included systematic reviews, meta-analysis, and studies is shown in Table 1 .

Table of mentioned systematic reviews, meta-analyses and important studies.

SA—systematic analysis; MA—meta-analysis; R—randomized; DB—double-blind; PC—placebo-controlled.

5.1. Symptomatic Therapy

5.1.1. serotonin norepinephrine reuptake inhibitors (snris).

Patients often respond well to SNRIs, and they are considered a first-line treatment by the AAN and the ADA. Both societies specifically mention venlafaxine, desvenlafaxine, and duloxetine as SNRI agents with varying levels of efficacy.

SNRIs work by inhibiting the serotonin transporter (SERT) and norepinephrine transporter (NET) proteins, which are responsible for removing these neurotransmitters from the synapse after they have been released. Additionally, SNRIs are believed to indirectly modulate other neurotransmitter systems, such as dopamine and acetylcholine, which may also contribute to their therapeutic effects [ 53 ].

In a Cochrane systematic review, a group of five trials had results favoring the usage of duloxetine compared to a placebo. Patients were pooled from the trials across multiple doses: 20 mg, 40 mg, 60 mg, or 120 mg per day. The review found that the relative rate of greater than 50% improvement in pain was 1.53 (95% CI). The paper further specified that the 20 mg-treated patients did not have a statistically significant change, but there was a paucity of data as only one trial had a 20 mg arm [ 35 ].

The statistical review carried out by the AAN in the writing of their guidelines found that duloxetine is moderately effective with moderate confidence, while desvenlafaxine was also found to be moderately effective with lower confidence [ 33 ].

A 2021 meta-analysis comparing the efficacy of duloxetine to gabapentin found no significant difference between the medications in terms of management of DPN pain. Moreover, the study suggested that the choice between these two groups is mostly based on cost-effectiveness (SNRIs being more expensive than gabapentionids), patients’ reports of side effects, and personal preference [ 36 ].

A 2023 systematic review showed similar results, further confirming the safety and efficacy of duloxetine in DPN pain treatment. The review also suggested that, considering the shorter list of side effects compared to pregabalin, it may serve as a preferential treatment. In addition, the review found that a dosage of duloxetine of 120 mg, compared to the regular 60 mg, can be given to patients to ensure pain relief without change in the frequency of side effect reports, further confirming its safety [ 37 ]. A recent systematic review found comparable results, proposing duloxetine as a preferential drug in comparison to gabapentin, due to the same levels of efficacy but better duloxetine tolerance [ 38 ].

It is worth noting that a 2017 meta-analysis comparing local capsaicin use to oral pain relief medication showed promising results. The study analyzed 25 randomized controlled trials, suggesting that a capsaicin 8% patch provides pain relief similar to that of oral duloxetine, while also being an adequate substitute for pregabalin and gabapentin. Moreover, the study suggests that the patches may have a better side-effect profile compared to oral medication, in part due to the method of administration [ 39 ].

5.1.2. Gabapentinoids

Gabapentinoids are a class of drugs that include gabapentin and pregabalin. The mechanism of action of gabapentinoids is thought to involve modulation of the activity of voltage-gated calcium channels. Specifically, gabapentinoids bind to the alpha2-delta subunit of these channels, which reduces calcium influx into neurons and thereby decreases the release of excitatory neurotransmitters such as glutamate and substance P [ 54 ]. This effect may account for their anticonvulsant properties as well as their ability to reduce neuropathic pain. Additionally, gabapentinoids have been shown to increase the synthesis and release of GABA, the primary inhibitory neurotransmitter in the central nervous system. This effect may also contribute to their anticonvulsant properties and may explain why they are effective in treating anxiety disorders [ 54 ].

The efficacy of pregabalin, which is FDA-approved for the treatment of painful diabetic neuropathy, has been shown to be high for both the management of pain of common comorbidities that arise due to DPN, such as sleep interference [ 55 ]. Gabapentin has also been shown to have a pain-reducing effect, with one multicenter RCT showing a mean relief of 39% after 8 weeks [ 56 ].

Mirogabalin (DS-5565) is a new gabapentinoid recently brought onto the market in Japan. The drug has the same mechanism of action as other gabapentinoid medications, but has increased potency at the alpha2-delta subunit, as compared to pregabalin [ 57 ]. The following clinical trials indicate efficacy in the treatment of DPN.

A randomized double-blind trial specifically looking at patients with DPN showed that doses of mirogabalin between 15 and 30 mg/day led to significant reductions in pain when compared to a placebo at the 5-week mark [ 40 ]. The trial also had a single arm with patients randomized to 300 mg of pregabalin, and found no significant improvement in pain for patients. This trial can be found in Table 2 , with other recently completed trials researching DPN pain.

Table of completed trials of importance for DPN.

R—randomized; DB—double-blind; PC—placebo-controlled.

Another randomized, double-blind trial was conducted with 834 patients, all of whom had DPN. Patients were randomized to either a placebo group or a group who received a mirogabalin dose between 15 and 30 mg/day. In all groups, the average daily pain score did decrease over the course of the 14-week trial, but the final results only showed a statistically significant decrease for the group randomized to the 30 mg/day dose [ 41 ].

So far, all clinical trials involving mirogabalin have been performed in East Asian countries, and the medication is approved for usage in Japan. At this time, there is no indication if mirogabalin will undergo clinical trial for DPN elsewhere.

5.1.3. Sodium Channel Blockers

Sodium channel blockers are a class of drugs that target the voltage-gated sodium channels found in neurons and cardiac cells. These channels are responsible for generating and propagating action potentials, which are essential for the transmission of signals in the nervous and cardiovascular systems. Sodium channel blockers work by binding to the channel pore and preventing the influx of sodium ions, which results in the inhibition of action potential generation and propagation. Sodium channel blockers that are currently used in the treatment of pain are drugs that are also used as anesthetics, class 1 antiarrhythmics, anti-convulsants (such as oxcarbazepine), and tricyclic antidepressants [ 58 ].

Sodium channel inhibition can be selective or non-selective, depending on the specific drug and the type of sodium channel being targeted. For example, some drugs, such as lidocaine, selectively block channels that are in an activated or inactivated state.

On the other hand, drugs such as tetrodotoxin (TTX) selectively inhibit specific isoforms of sodium channels. This discovery led to the categorization of nine known isoforms of sodium channels into two groups, TTX-sensitive and TTX-resistant. Isoforms Na V 1.1, Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.6, and Na V 1.7 are TTX-sensitive, with their predominant location being on the central and peripheral neurons, with the exception of Na V 1.4 being mostly found in skeletal muscle. The remaining three isoforms are TTX-resistant and expressed in cardiac muscle (Na V 1.5) and the dorsal root ganglion neurons (Na V 1.8 and Na V 1.9) [ 59 ]. This range in sensitivity amongst the sodium channels is due to a difference in the amino acid sequence that makes the binding site for TTX, leaving some of them resistant to this sodium channel inhibitor [ 60 ].

While in some clinical applications, broad-spectrum blockade is favorable, only certain sodium channels have been implicated in nociceptive pathways and, therefore, are preferable to selectively inhibit to avoid systemic side effects [ 58 ].

A Na V 1.7 isoform of the sodium channel has been the target of extensive research in previous years due to the fact that a loss of function mutation of the gene that encodes this isoform results in total body insensitivity to pain. This discovery lead researchers to believe that a selective inhibition of this channel might prove beneficial in pain treatment in various pathological states [ 61 , 62 ].

Multiple studies have suggested that a group of molecules called arylsulfonamides could play a significant role in finding a specific inhibitor of the Na V 1.7 isoform [ 63 , 64 ]. Moreover, certain sodium channel blockers such as lidocaine have been shown to enhance the inhibitory effect arylsulfonamides have on Na V 1.7 channels. [ 65 ] Due to the very similar structure of these channels and their abundance in different tissues throughout the body, the search for a specific inhibitor is proving to be difficult, and more extensive research is needed in the field.

Both the AAN and ADA have sodium channel blockers as listed therapy options for the treatment of DPN, with the AAN specifically stating they have a moderate confidence in the data cited in their review [ 33 ].

A 2020 systematic review analyzing 43 randomized controlled trials showed that a lidocaine 700 mg medicated plaster was equivalently efficient in peripheral neuropathic pain management compared to pregabalin, yet had a better adverse event profile [ 42 ].

5.1.4. Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are a class of drugs that were among the first antidepressants to be developed and widely used. The mechanism of action of TCAs is complex, but they primarily act by inhibiting the reuptake of the monoamine neurotransmitters, including norepinephrine, serotonin, and dopamine, back into presynaptic neurons. This results in an increased concentration of these neurotransmitters in the synaptic cleft, which enhances neurotransmission and mood stabilization. Additionally, TCAs are known to block various receptors, including histamine, alpha-adrenergic, and muscarinic receptors, which may contribute to their clinical effects and side effects [ 43 ].

TCAs are considered second-line to SNRIs when it comes to neuropathic pain [ 66 ]. TCAs can be successfully used as monotherapy for neuropathic pain, but their adverse event profile can be more burdensome to patients compared to SNRIs [ 67 ]. Moreover, a dose greater than 75 mg daily is not recommended for patients over the age of 65 because of the dose-dependent anticholinergic side effects and an increased risk of falling [ 68 ].

Amongst a vast body of literature detailing this point, a newer 2020 systematic review of 18 placebo-controlled trials further confirmed that SNRIs are a preferential treatment for neuropathic pain, leaving TCAs as an alternative option [ 43 ].

A 2022 network meta-analysis looking at fibromyalgia treatment further corroborates these statements, showing that even though amitriptyline was associated with improvement in quality of life, fatigue, and pain, to some degree, duloxetine 120 mg (SNRI) was found to be more beneficial [ 44 ].

In a recent meta-analysis, 16 out of 18 placebo-controlled trial comparisons were positive for TCA use in chronic neuropathic pain, with the combined number needed to treat being 3.6, further confirming the use of TCAs in these patients [ 45 ].

The 2022 multicenter, crossover OPTION-DM trial studied the efficacy of different combinations of drugs used in the treatment of DPN. Over the course of 50 weeks, all patients enrolled underwent therapy with different treatment pathways, testing both monotherapies and combination therapy if patients did not have adequate pain relief. The study showed that supplementing amitriptyline with pregabalin (amongst other supplementation combinations) resulted in no statistically significant difference in diabetic neuropathy pain management outcome compared to other treatment combinations (including amitriptyline, pregabalin, and duloxetine). Furthermore, the study illustrated that current therapeutics alone are not adequate for a large number of patients, as monotherapy did not provide significant pain relief for about two thirds of trial participants. Although the study did give credibility to the usage of combination therapy, as it was generally more efficacious, the study also showed that a significant number of patients did not reach adequate levels of pain reduction with any combination, showing the need for new therapies [ 46 ].

5.2. Pathogenesis-Based Therapy

5.2.1. glp-1.

The options available in the treatment of diabetes have recently expanded with glucagon-like peptide-1 (GLP-1) agonists, which operate via the modulation of the incretin hormonal system. This system normally operates via the enteroendocrine system in a periprandial fashion. As a bolus of food is ingested, GLP-1 is released from secretory granules by intestinal L cells both through a neural signaling pathway via gastrin-releasing peptide (GRP) and acetylcholine, and eventually through L-cell direct contact interaction with the bolus of food. GLP-1 itself then can act on the GLP-1 receptor (GLP-1R), which is found on pancreatic islets, as well as throughout the GI tract, the vagus nerve, hypothalamus, and brainstem. Action on the pancreas leads to a stimulation of insulin release, while simultaneously inhibiting glucagon release and slowing gastric emptying. GLP-1 is then degraded by dipeptidyl peptidase-4 (DPP-4), as well as other endopeptidases [ 69 ].

Therefore, drugs that act to modulate this system either operate by mimicking GLP-1 or delaying endogenous GLP-1 degradation via inhibition of DPP-4. Drugs recently brought to market include semaglutide, lixisenatide, dulaglutide, liraglutide, and exenatide.

Tirzepatide is a GLP-1 agonist that is a modified analog of gastric inhibitory peptide (GIP). It has been demonstrated that tirzepatide has stronger affinity for the GIP receptor than the GLP-1 receptor. This dual mechanism of action still acts to promote insulin secretion, but has different pharmacodynamic properties, which have been shown to be beneficial in terms of improving insulin sensitivity, as well as reducing obesity [ 70 ].

Furthermore, retatrutide, a GLP/GIP/glucagon triple agonist, with limited but promising data, is another medication being brought to market [ 71 ]. As with the current treatments for DPN, future trials testing the effects of these multi-receptor incretin mimetics on DPN are still needed.

If a provider feels that a patient is a good candidate for GLP-1 agonist treatment, then lab testing and patient history guide the selection of which specific agent is appropriate. Half-lives vary dramatically, with current market formulations lasting between 2.4 h and a week [ 72 ]. A review of different GLP-1 agonists found that longer-acting agents are more effective at improving glycemic control.

A meta-analysis of 34 RCTs showed that GLP-1 agonists of all formulations are very effective at lowering HbA1c, with treatments ranging between 0.55% and 1.21%; dulaglutide and liraglutide had the greatest reduction of 1.21% and 1.15% on average, respectively [ 47 ].

Possible Role of GLP-1 Agonists in the Treatment/Prevention of Ongoing Diabetic Neuropathy

GLP-1 agonists have recently come onto the market for the treatment of diabetes, and as previously mentioned, DPN is a frequent complication of diabetes. A 2022 meta-analysis that included 101,440 patients treated with either sodium–glucose co-transporter 2 (SGLT-2) inhibitors or GLP-1 agonists was studied to see if there were major adverse limb events in either group. After analysis was performed, the authors concluded that GLP-1 agonist use can be associated with significantly reduced risks of adverse limb events [ 48 ].

Another 2022 meta-analysis aimed to compare lower extremity amputation rates in patients treated with SGLT-2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists. Based on their analysis of eight retrospective case–control designs, they found no advantage of either category in terms of limb loss rates [ 73 ]. In the following sections, the methods by which GLP-1 agonists may contribute to the treatment of DPN are outlined.

Microvascular Disease

In the pathogenesis of diabetes patients, high circulating sugars can lead to oxidative stress, as previously mentioned, but also to dysfunction of the endothelium in blood vessels. This process can occur anywhere, but would be of significant concern in the microvasculature that feeds nerve fibers. This process can lead to ischemia of the nerve, causing functional changes within the nerve, and eventually loss of the nerve fiber itself. Although peripheral neuropathy is the most common, autonomic and cranial nerve neuropathies are seen as well [ 74 ].

A cross-sectional study of newly diagnosed type 2 diabetics in Vietnam that studied the relationship between cardiovascular risk factors and the development of DPN found that smoking and poor control of HbA1C correlated with DPN, while body mass index, dyslipidemia, drinking, and hypertension did not have a direct relationship. Interestingly, the study found a statistically significant difference in levels of fasting GLP-1 patients who had developed DPN compared with patients who did not. The study found that there was, on average, an approximately 1.5 pmol/L decrease in GLP-1 levels among only the male patients who had DPN [ 49 ].

A review article by Bakbak et al. summarizes recently completed animal model trials that elucidated a relationship between GLP-1 agonism and the proliferation of new vasculature. The paper goes on to state that a limited number of trials have shown the GLP-1 agonism to be a mechanism to prevent endothelial dysfunction in type 2 diabetics with decreased peripheral circulation, a common factor leading to DPN [ 75 ].

Recent studies have shown a relationship between the prescription of GLP-1 agonists and an increase in cardiovascular health. The LEADER trial, which tested liraglutide, as well as the SUSTAIN-6 trial, testing semaglutide, compared these drugs to standard diabetic care via monitoring risk markers for cardiovascular disease [ 50 , 51 ]. Both studies showed that these medications lowered the risk of adverse cardiovascular events. While this is not a direct statement of these medications’ ability to reverse or prevent neuropathy in diabetics, it is possibly a sign that these medications may have a potential role in preventing new neuropathy via decreasing stress on the vasa nervorum. This may be because GLP-1 has been seen to decrease reactive oxygen species production and decrease vascular cell adhesion molecule-1 expression [ 76 ], in turn preventing endothelial inflammatory responses [ 77 ].

Nerve Fiber Repair

As previously mentioned, the pathogenesis of DPN is multifactorial, and all factors eventually coalesce as damage to nerve fibers. This damage in turn leads to the hyperexcitability of nociceptors, causing pain in patients with DPN. Several trials have studied the relationship between GLP-1 agonism and the possible respiration of the factors required in the process of repairing a damaged but not yet apoptotic nerve.

In one trial, rats were exposed to streptozotocin to induce diabetes. Diabetic rats were trialed on 1 nmol/kg/day doses of extendin-4, a GLP-1 agonist endogenous in gila monsters. The trial studied the perception threshold in the limbs of the treated rats as compared to rats not given extendin-4. Perception thresholds were quantified using a nerve stimulator set to a fixed frequency. The study found that over the course of 24 weeks, the control group not given extendin-4 gradually developed higher perception thresholds, while the experimental group maintained their initial values. After the trial concluded, the rats were sacrificed, and immunohistochemical staining of nerve fibers found that in extendin-4-treated rats, Schwann cell apoptosis was prevented and myelinated fiber size was maintained. Of note, the authors found that due to the near complete destruction of the pancreas via streptozotocin, the extendin-4 agonist was unable to modulate glucose control via increased insulin secretion. This would imply that the neuroprotection provided by extendin-4 in this trial is likely not due to the normal glucose-lowering effects of GLP-1 agonists, but rather direct agonism of the GLP-1 receptor on the nerve itself [ 78 ].

A similar trial was performed with liraglutide on rats that had streptozotocin-induced diabetes after 8 weeks of acclimation. Once again, the trial found that daily dosing of liraglutide for 8 weeks improved nerve health. The nerve conduction velocity was measured in the sciatic nerve of the rats throughout the trial. At the conclusion of the trial, the rats’ nerves showed signs of improved myelination under histological staining [ 79 ].

A 2015 pilot study randomized patients to exenatide or insulin glargine to evaluate the effect of exenatide on DPN symptoms in type 2 diabetics with DPN. The trial followed the progression of patient’s symptoms of DPN as well as their peripheral nerve conduction values and epidermal nerve fiber density. The trial concluded having found no significant differences in the GLP group as compared to the insulin patients in any of their measured categories [ 80 ].

A 2020 study randomized patients with poorly controlled T2D to receive exenatide and pioglitazone or insulin aspart and glargine. After following up with patients at the one-year mark, it was found that both groups showed corneal nerve regeneration compared to baseline. The study did not show any difference in DPN symptoms or metrics in either group compared to baseline [ 81 ].

In a 2021 study performed in Australia, patients receiving exenatide, a DPP-4 inhibitor, or a SGLT-2 had their motor nerve excitability tested as compared to healthy controls. The exenatide arm of the study was found to have normal nerve excitability as compared to DPP-4- or SGLT-2-treated patients. The researchers then wanted to further assess the effect of exenatide, and performed a prospective analysis with a smaller group of subjects. This second part of the study compared subjects before and 3 months after the start of treatment with exenatide. At the conclusion of the trial, the researchers found a statistically significant improvement in all three of their measures of nerve excitability as compared to baseline recordings in study subjects. Furthermore, the study found that there was no correlation between the percent improvement in HbA1c or blood pressure and the change in nerve excitability [ 52 ].

It should be noted that all of these trials have relatively small sample sizes, as the largest experimental group among all three trials was 90 patients. Furthermore, each trial recruited patients at different stages of progression in their DPN, indicating that the stage of pathogenesis potentially impacts the efficacy of the treatment.

Although these trials have mixed results, there are still no large-scale clinical trials of GLP-1 agonists in patients with DPN. Additionally, the mechanism by which GLP-1 agonists participate in nerve homeostasis has still not been fully elucidated. At this time, there is no definitive conclusion to be drawn as to if GLP-1 agonists are useful in the treatment of neuropathy, but the current research does offer promise in their usage looking forward.

5.2.2. SGLT-2 Inhibitors

SGLT-2 inhibitors are another class of medications that have been theorized to have potential efficacy in the treatment of DPN. SGLT-2 inhibitors are used in the treatment of type 2 diabetes and act on the kidney to inhibit the reabsorption of glucose. Although there have been many clinical trials that have involved SGLT-2 inhibitors, the vast majority have not assessed outcomes related to DPN. As previously mentioned in this paper, meta-analyses have not found a correlation between the usage of SGLT-2 inhibitors and distal limb protectiveness. One analysis stated that GLP-1 agonists had a statistically significant reduction in adverse limb events as compared to SGLT-2 inhibitors [ 48 ]. This finding needs more supporting evidence, as another meta-analysis found no difference between SGLT-2 inhibitors and GLP-1 agonists when looking at limb amputation as a specific adverse limb outcome [ 73 ].

So far, no trials have looked at SGLT-2 inhibitors as a monotherapy for the treatment of DPN in diabetic patients. Looking to the future, there is currently one trial underway ( {"type":"clinical-trial","attrs":{"text":"NCT05162690","term_id":"NCT05162690"}} NCT05162690 ) that looks to test the efficacy of dapagliflozin in DPN.

In animal models, a few studies have shown some promising preliminary data. in one trial, the SGLT-2 inhibitor ipragliflozin was tested on rats to determine the effects on DPN. The rats were diabetic prior to the start of testing, and non-diabetic rats were used as a control. The study found that the conduction velocity of peripheral leg nerves improved after SGLT-2 inhibitor treatment [ 82 ].

A study that used streptozotocin to induce diabetes in rats showed that SGLT2 inhibitor therapy may have a role in slowing down the pathogenesis of DPN via reversing risk factors such as oxidative stress, inflammation, and glucotoxicity [ 83 ]. Another trial, which used empagliflozin in diabetic rats, found that SGLT2 inhibitor treatment prevented the loss of skin nerve fibers and peripheral hypersensitivity [ 84 ].

Although these trials generally do provide insight into the possible efficacy of SGLT-2 inhibitors in limiting DPN, the lack of clinical trials means that conclusions cannot be drawn as to the efficacy of these medications in humans.

6. Clinical Trials

As previously established, the chronic nature, high prevalence, and severity of pain in DPN makes this clinical entity a burden to both patients and the healthcare system. Taking this into account, it is safe to say that the search for the improvement of symptoms and quality of life in these patients is continuous. A vast array of clinical trials that are currently recruiting or have recently been completed show promising approaches to treatment. From opioid agonists, anti-inflammatory and anti-oxidant treatment to fusion proteins and vitamin analogs, future clinical trials are covering extensive possibilities for pain alleviation.

It should be noted that most of the recently completed clinical trials focus on the use of newer and previously less explored medication groups, such as monoclonal antibodies and different gene-recombinant products. These modern advances in pharmacological therapy have shown great promise in the field of DPN pain, taking into account some of the currently published results.

One of the completed trials was in phase 3, while the rest were completed in phase 2. The trials followed different measurements for classifying pain relief and management, including a 50% reduction in average daily pain, change from baseline in different pain scores, or daily interference scores. Some of the trials found the medication to be more safe than effective, whereas others could not draw a concrete conclusion. This is in part due to the fact that, as previously described in the review, the pathophysiology of DPN pain is multifactorial, complex, and highly individual among patients, making it harder to find an all-encompassing treatment regime.

Summaries of currently recruiting and completed clinical trials concerning DPN pain are shown in Table 2 and Table 3 , respectively.

Table of recruiting trials of importance for DPN pain.

7. Conclusions

In conclusion, we have summarized the current common pharmacological treatment options available for the treatment of diabetic peripheral neuropathy. We have also raised questions about the possible efficacy of treatments outside of the standard of care recommendations made by the ADA and AAN, such as capsaicin, GLP-1 agonists, and mirogabalin. Although GLP-1 agonists do not yet have enough trials to argue they are effective in treating diabetic peripheral neuropathy, they could be a promising intervention. Looking to the future, more research is needed to determine which patients respond best to each of these medications. Pharmacogenetic trials can help to understand why many patients must trial multiple medications before finding significant relief. Furthermore, it is unclear when in the pathogenesis of DPN a patient could be eligible for polypharmacy treatment plans, and future research can help to indicate the efficacy and interactions of multiple DPN medications together.

Abbreviations

List of abbreviations:

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, N.N.K.; writing review O.S. and P.J.; editing and supervision, N.N.K. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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