Amputation Risk in Type II Diabetes Mellitus Patients Treated with SGLT-2 Inhibitors: A Systematic Literature Review of Randomized Clinical Trials

Abstract

Background SGLT-2 inhibitors, prescribed for type 2 diabetes, have a heightened risk of amputation. The FDA issued a warning in May 2017, leading to the inclusion of a cautionary label. Vigilance is essential for patients and healthcare providers to promptly identify and address potential limb complications associated with the use of SGLT-2 inhibitors.

Method A comprehensive search of electronic databases was conducted, covering the period from inception to May 2024. This systematic literature review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the included studies was assessed using the Cochrane risk of bias (ROB) tool. Inclusion and exclusion criteria were predefined, and data extraction was performed to summarize the findings.

Result A total of 12 randomized control trial (RCT) studies were included in the present systematic review. 37,657 (54.89%) participants were randomly assigned to receive the different interventions of SGLT-2 inhibitor, whereas 30,959 (45.11%) received a placebo. Overall, 618 events were reported in the treatment group, whereas 396 events were reported in the placebo group.

Conclusion In conclusion, patients treated with SGLT-2 inhibitors did not have any significant difference in amputation occurrences compared to placebo across various studies. However, canagliflozin usage has led to higher amputation events in certain trials.

Keywords

amputations - diabetes - sodium-glucose cotransporter 2 inhibitors - SGLT-2 inhibitors - type 2 diabetes mellitus

Publication History

Received: 21 May 2024

Accepted: 09 July 2024

Article published online:
02 August 2024

• References

• 1 Vasilakou D, Karagiannis T, Athanasiadou E. et al. Sodium–glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Annals of internal medicine 2013; 159: 262-274
• 2 Idris I, Donnelly R. Sodium–glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes, Obesity and Metabolism 2009; 11: 79-88
• 3 Hussain S, Habib A, Najmi AK. Anemia prevalence and its impact on health-related quality of life in Indian diabetic kidney disease patients: evidence from a cross-sectional study. Journal of Evidence-Based Medicine 2019; 12: 243-252
• 4 Hussain S, Habib A, Singh A. et al. Prevalence of depression among type 2 diabetes mellitus patients in India: A meta-analysis. Psychiatry research 2018; 270: 264-273
• 5 Hussain S, Khan MS, Jamali MC. et al. Impact of bariatric surgery in reducing macrovascular complications in severely obese T2DM patients. Obesity Surgery 2021; 31: 1929-1936
• 6 Udell JA, Yuan Z, Rush T. et al. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor: results from the EASEL population-based cohort study (evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world). Circulation 2018; 137: 1450-1459
• 7 Garcia-Ropero A, Badimon JJ, Santos-Gallego CG. The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments. Expert Opinion on Drug Metabolism & Toxicology 2018; 14: 1287-1302
• 8 Markham A. Remogliflozin etabonate: first global approval. Drugs. 2019; 79: 1157-1161
• 9 Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018; 61: 2118-2125
• 10 Dekkers CC, Gansevoort RT, Heerspink HJ. New diabetes therapies and diabetic kidney disease progression: the role of SGLT-2 inhibitors. Current diabetes reports 2018; 18: 1-2
• 11 Singh M, Kumar A. Risks associated with SGLT2 inhibitors: an overview. Current drug safety 2018; 13: 84-91
• 12 Miyashita S, Kuno T, Takagi H. et al. Risk of amputation associated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of five randomized controlled trials. Diabetes Research and Clinical Practice 2020; 163: 108136
• 13 Neal B, Perkovic V, Mahaffey KW. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine 2017; 377: 644-657
• 14 US Food and Drug Administration. FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). https://www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf Updated May 16, 2017 Accessed April 11 2024
• 15 Chang HY, Singh S, Mansour O. et al. Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA internal medicine 2018; 178: 1190-1198
• 16 Bonaca MP, Beckman JA. Sodium Glucose Cotransporter 2 Inhibitors and Amputation Risk: Achilles’ Heel or Opportunity for Discovery?. Circulation 2018; 137: 1460-1462
• 17 Yuan Z, DeFalco FJ, Ryan PB. et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study. Diabetes, Obesity and Metabolism 2018; 20: 582-589
• 18 Page MJ, McKenzie JE, Bossuyt PM. et al The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. International journal of surgery 2021; 88: 105906
• 19 Hoda F, Khanam A, Thareja M. et al. Effect of Nigella Sativa in Improving Blood Glucose Level in T2DM: Systematic Literature Review of Randomized Control Trials. Drug Research 2023; 73: 17-22
• 20 Higgins JP, Altman DG, Gøtzsche PC. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj. 2011
• 21 Popay J, Roberts H, Sowden A. et al. Guidance on the conduct of narrative synthesis in systematic reviews. A product from the ESRC methods programme Version 2006; 1: b92
• 22 Heerspink HJ, Stefánsson BV, Correa-Rotter R. et al Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine 2020; 383: 1436-1446
• 23 Cannon CP, Pratley R, Dagogo-Jack S. et al Cardiovascular outcomes with ertugliflozin in type 2 diabetes. New England Journal of Medicine 2020; 383: 1425-1435
• 24 Bhatt DL, Szarek M, Steg PG. et al Sotagliflozin in patients with diabetes and recent worsening heart failure. New England Journal of Medicine 2021; 384: 117-128
• 25 Wiviott SD, Raz I, Bonaca MP. et al Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine 2019; 380: 347-357
• 26 Perkovic V, Jardine MJ, Neal B. et al Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine 2019; 380: 2295-2306
• 27 Pollock C, Stefánsson B, Reyner D. et al. “Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial.”. The Lancet Diabetes & Endocrinology 2019; 7: 429-441
• 28 McMurray JJ, Solomon SD, Inzucchi SE. et al Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine 2019; 381: 1995-2008
• 29 Neal B, Perkovic V, Mahaffey KW. et al Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine 2017; 377: 644-657
• 30 Nassif ME, Windsor SL, Tang F. et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation 2019; 140: 1463-1476
• 31 Lee MM, Brooksbank KJ, Wetherall K. et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation 2021; 143: 516-525
• 32 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New england journal of medicine 2015; 373: 2117-2128
• 33 Bhatt DL, Szarek M, Pitt B. et al. Sotagliflozin in patients with diabetes and chronic kidney disease. New England Journal of Medicine 2021; 384: 129-139
• 34 Johannesson A, Larsson GU, Ramstrand N. et al Incidence of lower-limb amputation in the diabetic and nondiabetic general population: a 10-year population-based cohort study of initial unilateral and contralateral amputations and reamputations. Diabetes care 2009; 32: 275-280
• 35 Yu OH, Dell’Aniello S, Shah BR. et al. Sodium–glucose cotransporter 2 inhibitors and the risk of below-knee amputation: a multicenter observational study. Diabetes care 2020; 43: 2444-2452
• 36 Kani R, Watanabe A, Miyamoto Y. et al. Comparison of effectiveness among different sodium-glucose cotransoporter-2 inhibitors according to underlying conditions: a network meta-analysis of randomized controlled trials. Journal of the American Heart Association 2024; 13: e031805
• 37 Zelniker TA, Wiviott SD, Raz I. et al 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. The Lancet 2019; 393: 31-39
• 38 Dorsey-Treviño EG, González-González JG, Alvarez-Villalobos N. et al Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and microvascular outcomes in patients with type 2 diabetes: systematic review and meta-analysis. Journal of endocrinological investigation 2020; 43: 289-304
• 39 Dicembrini I, Tomberli B, Nreu B. et al Peripheral artery disease and amputations with sodium-glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized controlled trials. Diabetes Research and Clinical Practice 2019; 153: 138-144
• 40 Heyward J, Mansour O, Olson L. et al. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis. PLoS One 2020; 15: e0234065
• 41 Li CX, Liang S, Gao L. et al. Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: a real-world systematic review and meta-analysis. PloS one 2021; 16: e0244689
• 42 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New england journal of medicine 2015; 373: 2117-2128
• 43 Vardeny O, Vaduganathan M. Practical guide to prescribing sodium-glucose cotransporter 2 inhibitors for cardiologists. JACC: Heart Failure 2019; 7: 169-172
• 44 American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes care 2017; 40: S64-S74
• 45 Lytvyn Y, Bjornstad P, Udell JA. et al. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation 2017; 136: 1643-58.
• 46 Yuan Z, DeFalco FJ, Ryan PB. et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study. Diabetes, Obesity and Metabolism 2018; 20: 582-589
• 47 Fralick M, Kim SC, Schneeweiss S. et al. Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study. BMJ 2020; 370: m2812