Ahmed, Kaleem

Kalra, Sanjay

Nadeem, Sarah

Rana, Masooma

English

eCommons@AKU

eCommons@AKU Section of Diabetes, Endocrinology and Metabolism Department of Medicine 6-1-2021 SGLT2i use in non-diabetics Sarah Nadeem Masooma Rana Kaleem Ahmed Sanjay Kalra Follow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_med_diabet_endocrinol_metab  Part of the Endocrine System Diseases Commons, and the Endocrinology, Diabetes, and Metabolism Commons 1693J Pak Med AssocIntroductionSodium Glucose Co-Transporter 2 inhibitors (SGLT2i), whichinclude canagliflozin, dapagliflozin, empagliflozin andertugliflozin, are insulin-independent oralantihyperglycaemic medications that uniquely reduceglucose reabsorption in the proximal convoluted tubulesof the kidney resulting in glycosuria and natriuresis. Thesedrugs are effective in the treatment of any stage of type 2diabetes, as they can be used in states of insulin resistanceand beta-cell dysfunction. There are a number of differentSGLTi available worldwide (see Table 1). In Pakistan, wecurrently have dapagliflozin and empagliflozin licensed bythe Drug Regulation Authority of Pakistan for use indiabetes. This paper aims to summarize unconventionalnon diabetic uses of SGLT2i that shown promising results.1Use of SGLT2 inhibitors in DiabetesThe 2019 guidelines from the American DiabetesAssociation recommend lifestyle modifications andmetformin as first line treatment to reach target HbA1c inpatients with type 2 DM; if these therapies fail to achievegoal then existing comorbidities should be consideredincluding cardiovascular disease, congestive heart failure,chronic kidney disease and obesity to guide the decisionfor treatment. SGLT2i are recommended as preferredadjunct therapy in these four conditions, if the patient hasan adequate estimated glomerular filtration rate (eGFR)4-7as SGLT2i have demonstrated multiple beneficial effectsalong with glucose lowering in a number of clinical trials.5-7Sodium Glucose Co-Transporter 2 (SGLT2) is an essentialprotein primarily responsible for physiological glucosereabsorption. It is responsible for 90 percent of glucoseuptake from proximal renal tubules, with SGLT1reabsorbing the remaining 10%. Inhibition of SGLT2 resultsin blockage of this glucose reabsorption mechanism,causing glycosuria and resulting lowered blood glucoselevels.8 A distinct benefit with their use is that their glucoselowering effect is independent of beta cell function orinsulin sensitivity thus carrying low risk for hypoglycaemiaas well as potential for use in Type 1 Diabetics (approved inEurope, rejected in the US by FDA).9 Since theirintroduction into clinical practice in 2013, SGLT2i  drugshave demonstrated improved glucose control, reducedblood pressure, significant reductions in HbA1c, andweight loss in persons with type 2 diabetes. Recent studies assessing the effects of SGLT2i on associatedcardiac and renal disease in diabetic patients have showncardiovascular risk reduction, decreased heart failuremortality and renal protective effects.10-12 EMPA-REGOUTCOME was the first trial on the renal benefits in thesedrugs—published in 2016—showing that empagliflozinwas associated with a slower progression of chronic kidneydisease and fewer renal complications in type 2 DMpatients with high cardiovascular risk.10 EMPA-REG alsodemonstrated reduced cardiovascular complications withempagliflozin, with a 38 percent risk reduction fromcardiovascular-related deaths in type 2 diabetics.11Dapagliflozin demonstrated reductions in cardiovascularhospitalizations and deaths in the DECLARE-TIMI trials.12Due to the success of SGLT2i in these settings, they arebeing considered for their potential cardiovascular benefitsin nondiabetics as well.  SGLT2i and Cardiovascular OutcomesAll SGLT2i have demonstrated significant risk reduction inhospitalization for heart failure13 yet a class effect on majorcardiovascular events (in studies so far) has not been seen.According to the DAPA-HF trial, dapagliflozin lowers the riskof worsening heart failure and cardiovascular related deathby 26 percent in patients with pre-existing heart failurewith a low ejection fraction, when compared to placebo;regardless if the patient has diabetes or not.14 The positiveRECENT ADVANCES IN ENDOCRINOLOGYSGLT2i Use in Non-DiabeticsSarah Nadeem1, Masooma Rana2, Kaleem S. Ahmed3, Sanjay Kalra4,51-3Aga Khan University, Karachi, Pakistan; 4Department of Endocrinology,Bharti Hospital, Karnal, India. 5All India Institute of Medical Sciences,Rishikesh, India. Correspondence: Sanjay Kalra e-mail: brideknl@gmail.comTable-1: List of available SGLT2i worldwide and their respective year of approval by theUS Food and Drug Administration (FDA) and European Medicines Agency (EMA)2,3SGLT2i Body of Approval for Diabetics Year of ApprovalDapagliflozin FDA 2014EMA 2012Canagliflozin FDA 2013EMA PendingEmpagliflozin FDA 2014EMA 2014Ertugliflozin FDA 2017EMA 2017results of the DAPA-HF trial allowed for the dapagliflozin(Farxiga - AstraZeneca) to be the first SGLT2i to be approvedby the US Food and Drug Administration (FDA) for use innondiabetic heart failure patients with reduced ejectionfraction.15 Along with this, a recent study found thatcanagliflozin and empagliflozin showed a larger reductionin heart failure risk than other drugs for type 2 diabetes.16SGLT2i drugs are believed to be useful in the setting ofheart failure due to it being a diuretic and the resultingvolume reduction; however, there is still more research tobe done to see the other effects these drugs have in thesetting of heart failure. More trials looking at the effectsSGLT2i on the cardiovascular system are currentlyunderway, to DELIVER trial with results available in 2021 isassessing at dapagliflozin’s effects on patients with heartfailure but preserved ejection fraction.1,17Kidney diseaseDapagliflozin has shown beneficial effects on the renalsystem, with studies suggesting that it has a role indecreasing hyperfiltration, albuminuria, and tubular injuryin both diabetic and non-diabetic patients. SGLT2i causenatriuresis and increased sodium delivered to the maculadensa activates tubuloglomerular feedback which resultsin intraglomerular pressure reduction due to constrictionof the afferent arteriole, and decrease in the glomerularfiltration rate. Studies have shown that these drugs areassociated with decreased urinary proximal tubular injurybiomarkers and reduction in inflammation and fibrosisformation, further suggesting its direct effects on thekidney.18 This has led to the approval of SGLT2i worldwidefor the expanded indication of reducing risk for end-stagerenal disease in diabetic patients with chronic kidneydisease.15There is also promise with the combination therapy of reninangiotensin system (RAS) blockers and SGLT2i in non-diabetic patients with proteinuria, as RAS blocker therapycan be insufficient in many patients, leading to worseningkidney function - as there would be a reduction of theglomerular filtration rate, and subsequent inhibition of theRAS.19 In current non-diabetic rat and mice models, resultshave been seen to vary. Other theories regarding therenoprotective effects of SGLT2i are attributed to adecrease in blood pressure, weight loss, and glycaemiccontrol. Clinical trials are required to determine if the renalbenefits of dapagliflozin are independent from theantihyperglycaemic effects.18 One trial was stopped earlier,in March 2020 by AstraZeneca; The Dapagliflozin AndPrevention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) Phase III trial for dapagliflozin in patients withchronic kidney disease (CKD) with and without Diabetestype 2 demonstrated overwhelming efficacy and benefitsearlier than originally anticipated.ObesityThese drugs may have a role to play potentially as obesitytreatment independent of diabetes as well. When usedalone, the glucose/calorie loss in the urine is not enoughto off-set food intake and yield significant weight loss.However, a number of studies have shown that whenSGLT2i are taken adjuvantly with other agents that reduceappetite, there is a greater reduction in body weight. GLP1-RA coupled with SGLT2i have demonstrated moderateweight loss in the range of 4.5-5.7kg in patients withoutdiabetes.20 A clinical trial also showed meaningfulreductions in body weight in obese non-diabetic patientswhen on canagliflozin and phentermine either incombination or each drug alone.21Other benefitsSGLT2i may also have a unique role in the prevention ofearly stage, well-differentiated lung adenocarcinoma andprecancerous lung lesions, as recent studies have shownSGLT2 expression and activity in these tumours.Canagliflozin was seen to have a role in increasing survivalrates in mice by limiting glucose supply in these cells.Modified PET scans were used in the study to assess theactivity of SGLT2, which has the potential to be useful indiagnosis of early lung cancers. However, the study hadlimitations concerning the fact that the therapeutic effectsof canagliflozin were reversible due to upregulation ofSGLT2. Along with this, the results of the study cannot beattributed to the knockout of SGLT2 in the cancer alone,and survival rates can be due to lowering of blood glucoserather than the inhibition of glucose uptake in thetumour.22Adverse effectsSGLT2i may cause the following adverse effects, althoughrare. There is an increased risk of genital tract infections andlower limb amputation with the use of SGLT2i. Genital tractinfections are seen twice as many times in patients takingSGLT2i when compared to placebo groups, but many ofthese cases were seen to be manageable.7 The CANVAS trialfound that canagliflozin increased the risk of lower limbamputation by 97%; however, empagliflozin had no suchassociations.1 Volume depletion may contribute todecreased circulation in the distal artery beds, leading toincreased risk for amputation. Genitourinary infections mayoccur due to glycosuria, warm/moist environment anddecreased immunity in diabetics (mild/moderateinfections); however, most patients did not require theneed to discontinue medicines and were manageable.1Patients with lowered eGFR (<30 mL/min/1.73m2) shouldnot be started on these drugs, and if eGFR declines, then1694Vol. 71, No. 6, June 2021SGLT2i Use in …….1695J Pak Med AssocM. Rana, K.S. Ahmed, S. Nadeem, et al.therapy should be discontinued as the efficacy and safetyof empagliflozin have not been established in patients withsevere renal impairment.ConclusionSGLT2i uniquely reduces glucose reabsorption in theproximal convoluted tubules of the kidney resulting inglycosuria and natriuresis. The indications for their usecontinue to expand rapidly from patients with diabetes toheart failure and CKD, with others likely to be added in thefuture.References 1. Simes BC, Mac Gregor GG. Sodium-Glucose Cotransporter-2 (SGLT2)Inhibitors: A Clinician’s Guide. Diabetes, Metabolic Syndrome andObesity: Targets and Therapy. 2019. 2. Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T,et al. Discovery of canagliflozin, a novel C-glucoside with thiophenering, as sodium-dependent glucose cotransporter 2 inhibitor for thetreatment of type 2 diabetes mellitus (1). J Med Chem. 2010;53:6355-60 3. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, SharpDE, et al. Empagliflozin, a novel selective sodium glucose cotrans-porter-2 (SGLT-2) inhibitor: Characterisation and comparison withother SGLT-2 inhibitors. Diabetes, Obes Metab. 2012;14:83-90 4. Johnson EL, Feldman H, Butts A, Billy CDR, Dugan J, Leal S, et al. Stan-dards of medical care in diabetes—2019 abridged for primary careproviders. Clin Diabetes. 2019;37: 11-34 5. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glu-cose co-transport-2 inhibitors in type 2 diabetes: A meta-analysis ofrandomized clinical trials. Diabetes, Obes Metab. 2014;16:457-466 6. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Effi-cacy and safety of sodium-glucose co-transporter-2 inhibitors intype 2 diabetes mellitus: systematic review and network meta-analy-sis. Diabetes, Obes Metab. 2016;18:783-94 7. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: Rationaleand clinical prospects. Nature Reviews Endocrinology. 2012;8:495-502 8. Mogensen CE. Maximum tubular reabsorption capacity for glucoseand renal hemodynamics during rapid hypertonic glucose infusionin normal and diabetic subjects. Scand J Clin Lab Invest. 1971;28:101-109 9. Europe embraces, FDA rejects use of SGLT inhibitors for type 1 dia-betes [Internet]. [cited 2020 Jul 12]. Available from:https://www.healio.com/news/endocrinology/20190723/europe-embraces-fda-rejects-use-of-sglt-inhibitors-for-type-1-diabetes10. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Von Eynatten M,Mattheus M, et al. Empagliflozin and progression of kidney diseasein type 2 diabetes. N Engl J Med. 2016;375:323-34 11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 di-abetes. N Engl J Med. 2015;373:2117-28 12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Da-pagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl JMed. 2019; 380:347-35713. Giugliano D, Esposito K. Class effect for SGLT-2 inhibitors: A tale of 9drugs. Cardiovasc. Diabetol. 2019:18:9414. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Mar-tinez FA, et al. Dapagliflozin in patients with heart failure and re-duced ejection fraction. N Engl J Med. 2019; 381:1995-200815. Farxiga approved in the US for the treatment of heart failure in pa-tients with heart failure with reduced ejection fraction [Internet].[cited 2020 Jul 12]. Available from:h t t p s : / / w w w. a s t r a z e n e c a . c o m / m e d i a - c e n t r e / p r e s s -releases/2020/farxiga-approved-in-the-us-for-the-treatment-of-heart-failure-in-patients-with-heart-failure-with-reduced-ejection-fraction.html16. Kramer CK, Ye C, Campbell S, Retnakaran R. Comparison of New Glu-cose-Lowering Drugs on Risk of Heart Failure in Type 2 Diabetes: ANetwork Meta-Analysis. JACC Hear Fail [Internet]. 2018 Oct 1 [cited2020 Jul 12];6(10):823–30. Available from:https://pubmed.ncbi.nlm.nih.gov/30196071/17. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PRe-served Ejection Fraction Heart Failure. - Full Text View -ClinicalTrials.gov [Internet]. [cited 2020 Jul 12]. Available from:https://clinicaltrials.gov/ct2/show/NCT03619213?term=da-pagliflozin&cond=heart+failure+with+preserved+ejection+frac-tion&rank=118. Vergara A, Jacobs-Cachá C, Soler MJ. Sodium-glucose cotransporterinhibitors: Beyond glycaemic control. Clin Kidney J. 2019;12:322-32519. Perico N, Ruggenenti P, Remuzzi G. ACE and SGLT2 inhibitors: the fu-ture for non-diabetic and diabetic proteinuric renal disease. CurrOpin Pharmacol. 2017;33:34-4020. Lundkvist P, Pereira MJ, Katsogiannos P, Sjöström CD, Johnsson E,Eriksson JW. Dapagliflozin once daily plus exenatide once weekly inobese adults without diabetes: Sustained reductions in body weight,glycaemia and blood pressure over 1 year. Diabetes, Obes Metab.2017; 19:1276-128821. Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, VercruysseF, et al. Coadministration of canagliflozin and phentermine forweight management in overweight and obese individuals withoutdiabetes: A randomized clinical trial. In: Diabetes Care. 2017;40:632-639 22. Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, etal. Sodium-glucose transporter 2 is a diagnostic and therapeutic tar-get for early-stage lung adenocarcinoma. Sci Transl Med. 2018;10:eaat5933 doi: 10.1126/scitranslmed.aat5933.Table-2: Available SGLT2i in Pakistan.SGLT2i licensed for use in PakistanFormulation and dose FrequencyDapagliflozin 5mg Once a dayDapagliflozin 10mg Once a dayDapagliflozin 5mg in combination with metformin 850mg Twice a dayDapagliflozin 5mg in combination with metformin 1000mg Twice a dayEmpagliflozin 10mg Once a dayEmpagliflozin 25mg Once a dayEmpagliflozin 12.5mg in combination with metformin 500mg Twice a dayEmpagliflozin 12.5mg in combination with metformin 850mg Twice a dayEmpagliflozin 12.5mg in combination with metformin 1000mg Twice a day

SGLT2i use in non-diabetics

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SGLT2i use in non-diabetics

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