Abstract :
The increased prevalence of Diabetes mellitus, the comorbid associations and complications among the global population has led to a dependency for treatment options with multiple modalities. One such option is the SGLT2 inhibitor (SGLT2i) class of drugs. SGLT2i have been demonstrated to improve glycemic control while providing cardiovascular (CV) and renal benefits in patients with T2DM. SGLT2 inhibitors comprising of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin and remogliflozin are indicated in T2DM individuals with CV complications or chronic kidney disease (CKD). Although generally well tolerated, they pose some important safety concerns. The most common side effect of SGLT2i administration being Genital Mycotic Infections (GMI) and Symptomatic Volume Depletion. Meta-analysis and large clinical trials have reported an incidence of 2.5% to 6.5% of GMI, and a 4-6-fold increased risk of GMI among patients on SGLT2i.
This narrative review evaluates the recent literature on SGLT2i and the incidence and severity of GMI. The review aims to help guide health care professionals involved in clinical care for patients on SGLT2 inhibitors.
The existing literature evidence suggests that the GMI associated with SGLT2i therapy are generally mild and respond well to the conventional treatment. Major risk factors of infection are female, poor hygiene, prior infection, and uncircumscribed men. Perineal hygiene and treatment with standard antifungal agents could effectively decrease the incidence of such infections and may not warrant strict discontinuation of SGLT2i therapy. Active patient participation and awareness during treatment initiation is helpful in early recognition of symptoms and timely interventions.
Keywords :
Antifungals, Genito Mycotic Infections, Perineal Hygiene, Sodium-glucose transport protein 2 (SGLT2) inhibitors.References :
- Mani P, Vohra A, Jain S. SGLT-2 Inhibitors – A Systematic Review of their Extra-Glycaemic Benefits and Safety Profile. Journal of Evidence Based Medicine and Healthcare. 2021 May; 8: p. 1868–1874.
- Bailey CJ, Day C. The future of new drugs for diabetes management. Diabetes Research and Clinical Practice. 2019 September; 155: p. 107785.
- Dobrică EC, Găman MA, Cozma MA, Bratu O, Stoian AP, Diaconu C. Polypharmacy in Type 2 Diabetes Mellitus: Insights from an Internal Medicine Department. Medicina. 2019 August; 55: p. 436.
- AL-Musawe L, Martins AP, Raposo JF, Torre C. The association between polypharmacy and adverse health consequences in elderly type 2 diabetes mellitus patients$\mathsemicolon$ a systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2019 September; 155: p. 107804.
- McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. The American Journal of Medicine. 2019; 132: p. S49–S57.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015; 373: p. 2117–2128.
- Neal B, Perkovic V, Mahaffey KW, De Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine. 2017; 377: p. 644–657.
- Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019 January; 380: p. 347–357.
- Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes, Obesity and Metabolism. 2016; 18: p. 783–794.
- Wu JHY, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. The Lancet Diabetes & Endocrinology. 2016 May; 4: p. 411–419.
- Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: Impact of pharmacologically-induced glucosuria. Diabetes Research and Clinical Practice. 2014 March; 103: p. 373–381.
- Adimadhyam S, Schumock GT, Calip GS, Marsh DES, Layden BT, Lee TA. Increased risk of mycotic infections associated with sodium–glucose co-transporter 2 inhibitors: a prescription sequence symmetry analysis. British Journal of Clinical Pharmacology. 2018 November; 85: p. 160–168.
- Goswami R, Dadhwal V, Tejaswi S, Datta K, Paul A, Haricharan RN, et al. Species-specific Prevalence of Vaginal Candidiasis Among Patients with Diabetes Mellitus and its Relation to their Glycaemic Status. Journal of Infection. 2000 September; 41: p. 162–166.
- Shubrook JH, Bokaie BB, Adkins SE. Empagliflozin in the treatment of type 2 diabetes: evidence to date. Drug design, development and therapy. 2015; 9: p. 5793.
- Triplitt C, Cornell S. Canagliflozin treatment in patients with type 2 diabetes mellitus. Clinical Medicine Insights: Endocrinology and Diabetes. 2015; 8: p. CMED–S31526.
- Novak LM, Kruger DF. Bolstering your armamentarium with SGLT2 inhibitors. The Nurse Practitioner. 2017; 42: p. 28–34.
- Scheen AJ. Pharmacodynamics, efficacy and safety of sodium–glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015; 75: p. 33–59.
- Fioretto P, Giaccari A, Sesti G. Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus. Cardiovascular diabetology. 2015; 14: p. 1–13.
- AstraZeneca 2. Farxiga prescribing information. [Online].; 2019 [cited 2020 July 27. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 202293s021lbl.pdf.
- Boehringer Ingelheim 2. Jardiance prescribing information. [Online].; 2018 [cited 2020 July 27. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/204629s023lbl.pdf.
- Janssen 2. Invokana prescribing information. [Online].; 2019 [cited 2020 July 27. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 204042s036lbl.pdf.
- Merck 2. Steglatro prescribing information. [Online].; 2019 [cited 2020 July 27. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 209803s002lbl.pdf.
- Toyama T, Neuen BL, Jun M, Ohkuma T, Neal B, Jardine MJ, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2019; 21: p. 1237–1250.
- DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nature Reviews Nephrology. 2017; 13: p. 11–26.
- Lu H, Lu H, Kosinski C, Wojtusciszyn A, Zanchi A, Carron PN, et al. SGLT2 Inhibitors, What the Emergency Physician Needs to Know: A Narrative Review. Journal of Clinical Medicine. 2021; 10: p. 2036.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015 November; 373: p. 2117–2128.
- Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine. 2019; 380: p. 2295–2306.
- Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, 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: p. 31–39.
- Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine. 2016; 375: p. 323–334.
- Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial. The lancet Diabetes & endocrinology. 2019; 7: p. 606–617.
- Neuen BL, Cherney DZ, Jardine MJ, Perkovic V. Sodium-glucose cotransporter inhibitors in type 2 diabetes: thinking beyond glucose lowering. Canadian Medical Association Journal. 2019 October; 191: p. E1128–E1135.
- Association AD, others. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes care. 2018; 41: p. S73–S85.
- Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia 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. 2018; 61: p. 2461–2498.
- Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. Journal of the American College of Cardiology. 2018; 72: p. 3200–3223.
- Lipscombe L, Booth G, Butalia S, Dasgupta K, Eurich DT, Goldenberg R, et al. Pharmacologic glycemic management of type 2 diabetes in adults. Canadian journal of diabetes. 2018; 42: p. S88–S103.
- Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017; 60: p. 1620–1629.
- Care D. Standards of medical care in diabetes 2019. Diabetes Care. 2019; 42: p. S124–138.
- Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal. 2019 August; 41: p. 255–323.
- Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes care. 2015; 38: p. 1638–1642.
- Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes, Obesity and Metabolism. 2014; 16: p. 457–466.
- Storgaard H, Gluud LL, Bennett C, Grøndahl MF, Christensen MB, Knop FK, et al. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PloS one. 2016; 11: p. e0166125.
- Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. Jama. 2018; 319: p. 1580–1591.
- Dave CV, Schneeweiss S, Patorno E. Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes, Obesity and Metabolism. 2019; 21: p. 434–438.
- Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Current medical research and opinion. 2012; 28: p. 1173–1178.
- Hirji I, Andersson SW, Guo Z, Hammar N, Gomez-Caminero A. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. Journal of diabetes and its complications. 2012; 26: p. 501–505.
- Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. 2013; 15: p. 613–621.
- Yabe D, Nishikino R, Kaneko M, Iwasaki M, Seino Y. Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events. Expert Opinion on Drug Safety. 2015 April; 14: p. 795–800.
- Yabe D, Hamamoto Y, Seino Y, Kuwata H, Kurose T, Seino Y. Sodium glucose co-transporter 2 inhibitor luseogliflozin in the management of type 2 diabetes: a drug safety evaluation. Expert Opinion on Drug Safety. 2017 August; 16: p. 1211–1218.
- Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. Journal of Diabetes and its Complications. 2013; 27: p. 479–484.
- Bailey CJ, Morales Villegas EC, Woo V, Tang W, Ptaszynska A, List JF. Efficacy and safety of dapagliflozin monotherapy in people with type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial. Diabetic Medicine. 2015; 32: p. 531–541.
- Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes, Obesity and Metabolism. 2013 January; 15: p. 432–440.
- Kumar KMP, Mohan V, Sethi B, Gandhi P, Bantwal G, Xie J, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India. Indian Journal of Endocrinology and Metabolism. 2016; 20: p. 372.
- Bode B, Stenlöf K, Harris S, Sullivan D, Fung A, Usiskin K, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes, Obesity and Metabolism. 2015 January; 17: p. 294–303.
- Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes, Obesity and Metabolism. 2013 January; 15: p. 372–382.
- Kohler S, Salsali A, Hantel S, Kaspers S, Woerle HJ, Kim G, et al. Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes. Clinical Therapeutics. 2016 June; 38: p. 1299–1313.
- Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes, Obesity and Metabolism. 2017; 19: p. 348–355.
- Sorensen MD, Krieger JN. Fournier’s gangrene: epidemiology and outcomes in the general US population. Urologia internationalis. 2016; 97: p. 249–259.
- Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium–glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Annals of Internal Medicine. 2019; 170: p. 764–769.
- FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. [Online].; 2018 [cited 2020 January 13. Available from: https://www.fda.gov/drugs/drug-safety-andavailability/fda-warns-about-rare-occurrences-seriousinfection-genital-area-sglt2-inhibitors-diabetes.
- Ghosh M, Rodriguez-Garcia M, Wira CR. The immune system in menopause: pros and cons of hormone therapy. The Journal of steroid biochemistry and molecular biology. 2014; 142: p. 171–175.
- Shrivastav VK, Shukla D, Shrivastav A, Jana AM, others. Prevalence of vaginal candidiasis in diabetic women of Madhya Pradesh, India. International Journal of Current Microbiology and Applied Sciences. 2015; 4: p. 834-46.
- Nyirjesy P, Sobel J, Fung A, Gassmann-Mayer C, Ways K, Usiskin K. Genital mycotic infections with canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM). In Diabetes; 2013. p. A276–A276.
- Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes, Obesity and Metabolism. 2013; 15: p. 432–440.
- Nichols GA, Brodovicz KG, Kimes TM, Déruaz-Luyet A, Bartels DB. Prevalence and incidence of urinary tract and genital infections among patients with and without type 2 diabetes. Journal of Diabetes and its Complications. 2017 November; 31: p. 1587–1591.
- Williams SM, Ahmed SH. 1224-P: Improving compliance with SGLT2 inhibitors by reducing the risk of genital mycotic infections: the outcomes of personal hygiene advice. 2019..
- Fungal diseases: candidiasis. Accessed May 24, 2020. https://www.cdc.gov/ fungal/diseases/candidiasis/index.html. 2020.
- Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian journal of endocrinology and metabolism. 2012; 16: p. S27.
- Wilding JPH, Woo V, Rohwedder K, Sugg J, Parikh S, Group D0S. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes, Obesity and Metabolism. 2014; 16: p. 124–136.
- Van Schalkwyk J, Yudin MH, Allen V, Bouchard C, Boucher M, Boucoiran I, et al. Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. Journal of Obstetrics and Gynaecology Canada. 2015; 37: p. 266–274.
- Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2016; 62: p. e1–e50.
- Edwards SK. European guideline for the management of balanoposthitis. International Journal of STD & AIDS. 2001 October; 12: p. 68–72.
- Kalra S, Baruah MP, Sahay R. Medication counselling with sodium glucose transporter 2 inhibitor therapy. Indian journal of endocrinology and metabolism. 2014; 18: p. 597.
- Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. The Lancet. 2010 June; 375: p. 2223–2233.
- McGill JB, Subramanian S. Safety of Sodium-Glucose Co-Transporter 2 Inhibitors. The American Journal of Cardiology. 2019 December; 124: p. S45–S52.