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Use of SGLT2 inhibitors during Ramadan: An expert panel statement

Open AccessPublished:September 21, 2020DOI:https://doi.org/10.1016/j.diabres.2020.108465

      Abstract

      Fasting from dawn to sunset, during the holy month of Ramadan, constitutes one of the five main pillars in Islam and is observed by the majority of Muslims. Owing to important physiological changes, Ramadan fasting holds a crucial place in the context of diabetes management. Approximately one-fifth of the world’s Muslim population resides in the Middle East and Africa (MEA) region. To discuss the challenges and management of diabetes during Ramadan fasting in the MEA region, a panel of 12 experts in the field of diabetes from across the MEA region attended two expert committee meetings held in Dubai. The key point of discussion was the safety and efficacy of the use of sodium–glucose co-transporter 2 inhibitors (SGLT2i) during Ramadan, based on outcomes of the recent clinical trials with SGLT2i. This is the first consensus recommendation on the management of diabetes with SGLT2i across the MEA region during Ramadan. The document summarizes expert views and opinions on the current management of diabetes with SGLT2i during Ramadan and aims to enhance the current knowledge and understanding on the issue of diabetes management during Ramadan. This will aid the physicians of the MEA region with appropriate decision-making for their patients during Ramadan.

      Keywords

      1. Introduction

      Approximately one-fifth of the world’s Muslim population lives in the Middle East and North Africa (MENA) region (Fig. 1). Muslims comprise about 93% of the population of this region [

      World Muslim Population more Widespread than You Might Think_Pew Research Center; 2017. Available at: <https://www.pewresearch.org/fact-tank/2017/01/31/worlds-muslim-population-more-widespread-than-you-might-think/>. Accessed on: 10 February 2020.

      ]. In 2019, approximately 55 million adults aged 20–79 years in the MENA region were reported to have diabetes, and this figure is estimated to increase to 108 million people by 2045 [

      International Diabetes Federation_Diabetes in MENA. Available at: <https://www.idf.org/our-network/regions-members/middle-east-and-north-africa/diabetes-in-mena.html>. Accessed on: 10 February 2020.

      ]. Hence, it is essential that updated and evidence-based practice guidelines and recommendations are followed for the management of diabetes in this region.
      Figure thumbnail gr1
      Fig. 1Regional distribution of Muslim population, 2010
      [

      World Muslim Population more Widespread than You Might Think_Pew Research Center; 2017. Available at: <https://www.pewresearch.org/fact-tank/2017/01/31/worlds-muslim-population-more-widespread-than-you-might-think/>. Accessed on: 10 February 2020.

      ]
      .
      Fasting during the holy month of Ramadan constitutes one of the five main pillars in Islam, and Ramadan falls during the ninth month of the Islamic lunar calendar. It is obligatory for all healthy adult Muslims to fast during Ramadan. The duration of fasting varies from 12 to 20 h, with the average fasting period being 15 h [
      • Adnan Z.
      • Yunes A.R.
      • Ahmed M.S.
      • et al.
      Diabetic patients fasting during Ramadan: Ten years overview.
      ]. During this month-long fasting period, Muslims are required to abstain from using certain oral medications, drinking, consuming food, and smoking from dawn to sunset. During Ramadan, people usually eat two meals a day: one before dawn and the other after sunset [
      • Almalki M.H.
      • Alshahrani F.
      Options for controlling type 2 diabetes during Ramadan.
      ]. Although the sick are exempted by Islam from fasting, many diabetic patients still choose to fast during Ramadan, and in some cases, even against their doctor’s advice [
      • Almalki M.H.
      • Alshahrani F.
      Options for controlling type 2 diabetes during Ramadan.
      ]. Observing a fast during Ramadan results in important physiological conditions, owing to the change in mealtimes and sleep patterns. Thus, during Ramadan, there is a risk of occurrence of various diabetes-associated complications, such as diabetic ketoacidosis (DKA), hyperglycemia, hypoglycemia, dehydration, and thrombosis, making Ramadan fasting a crucial factor in the context of diabetes management [
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ,

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ].

      2. Methods

      In order to discuss persisting challenges in the management of diabetes during Ramadan in the MEA region, two expert panel meetings were held in Dubai (2018 and 2019) involving 12 experts in the field of endocrinology and diabetes from across MEA. The members of the panel were selected to best represent the breadth of knowledge and clinical experience in the field across the MEA region. The key purpose of these meetings was to discuss the optimal management of patients with diabetes during Ramadan, emphasizing the use of novel agents, viz. sodium–lucose co-transporter 2 (SGLT2i), based on the outcomes of recent clinical studies. The panel largely relied on the evidence emerging from relevant randomized clinical trials and observational studies available until April 2020. The present article represents a non-systematic review of diabetes management during Ramadan with SGLT2i, based on open discussion and the presentations at the two meetings, supplemented by additional literature and material provided by all the authors. In addition, this document also summarizes the expert panel views and opinions in this context.
      The expert panel meetings and subsequent drafting of the manuscript were funded by AstraZeneca, Middle East Africa. The manuscript was developed by the authors along with the medical writer. The draft was thoroughly revised and approved by all the authors.

      2.1 Existing guidelines on the management of diabetes during Ramadan

      Several guidelines are available regarding the management of diabetes during Ramadan. In 2005, the American Diabetes Association (ADA) issued guidelines for the management of diabetes during Ramadan, which were subsequently updated in 2010 [
      • Al-Arouj M.
      • Bouguerra R.
      • Buse J.
      • et al.
      Recommendations for management of diabetes during Ramadan.
      ,
      • Al-Arouj M.
      • Assaad-Khalil S.
      • Buse J.
      • et al.
      Recommendations for management of diabetes during Ramadan: Update 2010.
      ]. Later, in 2015, the International Group for Diabetes and Ramadan (IGDR) provided their recommendations; subsequently, a year later, the International Diabetes Federation and Diabetes and Ramadan International Alliance (IDF-DAR) and Ali et al. issued guidelines [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ,

      Ibrahim M, Abu Al Magd M, Annabi FA, et al. Recommendations for management of diabetes during Ramadan: Update 2015. BMJ Open Diab Res Care 2015;3(1):e000108.

      ,
      • Ali S.
      • Davies M.J.
      • Brady E.M.
      • et al.
      Guidelines for managing diabetes in Ramadan.
      ]. Finally, Diabetes Canada provided its position statement in 2017 [
      • Bajaj H.S.
      • Abouhassan T.
      • Ahsan M.R.
      • et al.
      Diabetes Canada Position Statement for People with Types 1 and 2 Diabetes who Fast During Ramadan.
      ]. Risk categorizations depending on patient characteristics are a key feature of most of these guidelines. Table 1 represents the risk stratification delineated by the IDF-DAR guidelines (Table 1) [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ]. All the guidelines have emphasized on pre-Ramadan patient education. Furthermore, a study has shown that individualized patient education helped type 2 diabetes patients improve glycemic and weight control and achieve safer fasting with lowered risk of adverse effects such as severe hypoglycemia and hospitalization [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ,
      • Al-Arouj M.
      • Bouguerra R.
      • Buse J.
      • et al.
      Recommendations for management of diabetes during Ramadan.
      ,

      Ibrahim M, Abu Al Magd M, Annabi FA, et al. Recommendations for management of diabetes during Ramadan: Update 2015. BMJ Open Diab Res Care 2015;3(1):e000108.

      ,
      • Ali S.
      • Davies M.J.
      • Brady E.M.
      • et al.
      Guidelines for managing diabetes in Ramadan.
      ,
      • Bajaj H.S.
      • Abouhassan T.
      • Ahsan M.R.
      • et al.
      Diabetes Canada Position Statement for People with Types 1 and 2 Diabetes who Fast During Ramadan.
      ,
      • McEwen L.N.
      • Ibrahim M.
      • Ali N.M.
      • et al.
      Impact of an individualized type 2 diabetes education program on clinical outcomes during Ramadan.
      ]. Almost all these guidelines recommend that SGLT2i can be considered safe to use during fasting. However, SGLT2i should be used with caution in patients at risk of ketoacidosis or dehydration, or elderly patients, those on diuretics or with renal impairment, or hypotensive individuals [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ,

      Ibrahim M, Abu Al Magd M, Annabi FA, et al. Recommendations for management of diabetes during Ramadan: Update 2015. BMJ Open Diab Res Care 2015;3(1):e000108.

      ,
      • Ali S.
      • Davies M.J.
      • Brady E.M.
      • et al.
      Guidelines for managing diabetes in Ramadan.
      ,
      • Bajaj H.S.
      • Abouhassan T.
      • Ahsan M.R.
      • et al.
      Diabetes Canada Position Statement for People with Types 1 and 2 Diabetes who Fast During Ramadan.
      ].
      Table 1Risk stratification and management of diabetes during Ramadan (Adapted from IDF-DAR Guidelines, 2016)6.
      Risk stratificationRisk factorsRecommendations on fastingAdditional comments
      Category 1: Very high risk(a) Severe hypoglycemia and/or diabetic ketoacidosis within 3 months prior to Ramadan

      (b) History of recurrent hypoglycemia or hypoglycemia unawareness

      (c) Event of hyperglycemic hyperosmolar coma within 3 months before Ramadan

      (d) Chronic dialysis or chronic kidney disease stages 4 and 5

      (e) Old age with health problems

      (f) Poorly controlled type 1 diabetes

      (g) Pregnancy with prior diabetes or gestational diabetes mellitus treated with SUs or insulin

      (h) Acute illness

      (i) Advanced macrovascular complications
      Must not fastIf patients insist on fasting, then the following measures must be followed:

      (a) Check their blood glucose regularly (SMBG)

      (b) Receive properly structured education

      (c) Be followed by a qualified diabetes team

      (d) Adjust medication dose according to recommendations

      (e) In case of hypo- or hyperglycemia, or worsening of other medical conditions, patients must be prepared to break their fast.
      Category 2: High risk(a) Type 2 diabetes patients with sustained poor glycemic control or well-controlled on mixed insulin or MDI

      (b) Patients with well-controlled type 1 diabetes

      (c) Pregnant patients with type 2 diabetes or gestational diabetes controlled by only diet or metformin

      (d) Stage 3 chronic kidney disease patients

      (e) Additional risk factors such as presence of comorbid conditions

      (f) Diabetic patients performing intense physical labor

      (g) Use of drugs likely to affect cognitive function
      Should not fast
      Category 3: Moderate/low riskWell-controlled type 2 diabetes mellitus patients treated with either lifestyle therapy, or basal insulin, or metformin, or acarbose, thiazolidinediones, SGLT2i, incretin-based therapy, or second-generation SUsCan fastPatients who observe fasting must receive proper education, check their blood glucose on a regular basis (SMBG), and adjust the dose of medication as per recommendations.
      IDF-DAR: International Diabetes Federation, and Diabetes and Ramadan International Alliance; SUs: Sulfonylureas; MDI: Multiple daily injections; SGLT2: Sodium-dependent glucose transporter-2; SMBG: Self-monitoring of blood glucose.
      Although much progress has been made in terms of achieving satisfactory glycemic control in diabetes during Ramadan, there are several unmet needs in the context of diabetes management, and as such, each patient is different in terms of his/her treatment needs. Indeed, treatment must be individualized with the use of appropriate clinical judgment [

      Introduction: Standards of Medical Care in Diabetes—2020. Diab Care 2020;43(Suppl 1):S1–S2.

      ]. The DAR guidelines do provide a template for diabetes management during Ramadan aiming at individualizing therapies. However, these guidelines should be updated regularly.

      2.2 SGLT2i in management of diabetes during Ramadan

      Selective inhibition of SGLT2 aids the normalization of plasma glucose levels in patients with diabetes. Inhibition of SGLT2 prevents renal glucose reabsorption and, in turn, enhances glucose excretion through the urine [
      • Meng W.
      • Ellsworth B.A.
      • Nirschl A.A.
      • et al.
      Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
      ]. At present, three inhibitors of SGLT2 (SGLT2i) are approved in the MEA region, viz. canagliflozin, dapagliflozin, and empagliflozin [
      • Wilding J.P.
      • Rajeev S.P.
      • DeFronzo R.A.
      Positioning SGLT2 inhibitors/incretin-based therapies in the treatment algorithm.
      ]. Besides possessing effective anti-hyperglycemic properties, SGLT2i are beneficial for addressing the metabolic components of diabetes (such as obesity and hypertension).

      2.3 Common safety concerns associated with SGLT2i

      As the use of SGLT2i during Ramadan is associated with a few safety concerns, such as the risk of ketoacidosis, postural hypotension, and dehydration, treatment with SGLT2i should be avoided in specific groups of patients, including those taking diuretics, hypotensive patients, or patients with renal impairment, or elderly patients [
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ]. Studies addressing various safety concerns associated with SGLT2i use during Ramadan have been summarized in Table 2.
      Table 2Clinical evidence on common safety concerns associated with SGLT2i during Ramadan.
      Study name/author, year and SGLT2i typeStudies on general safety concerns
      Dehydration/Volume depletionRenal effectsGenito-urinary infectionsDiabetic ketoacidosis and hyperglycemiaHypoglycemiaBone health and amputation
      DECLARE-TIMI 58, 2019
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      No change with dapagliflozin, as compared to placeboLower rate of progression of renal disease with dapagliflozin than placeboHigher rate of genital infections with dapagliflozin than placeboHigher rate of diabetic ketoacidosis with dapagliflozin than placeboFewer patients in the dapagliflozin group reported major hypoglycemia, as compared to placeboNo change in amputation and bone fracture rates with dapagliflozin, as compared to placebo
      DAPA-HF, 2019
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      No change with dapagliflozin, as compared to placeboNo change with dapagliflozin, as compared to placeboNo report of diabetic ketoacidosis eventsNo change with dapagliflozin, as compared to placeboNo change in amputation and bone fracture rates with dapagliflozin, as compared to placebo
      CREDENCE, 2019
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      Lower risk of kidney failure with canagliflozin, as compared to placeboOverall low rates of diabetic ketoacidosis reported, but relatively higher rates in canagliflozin group than placeboNo change in lower limb amputation and fracture rates with canagliflozin, as compared to placebo
      CANVAS, 2017
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      No change in volume depletion with canagliflozin, as compared to placeboBenefits in some renal outcomes observed with canagliflozin, though statistically insignificantNo increased risk of urinary infections, but higher rates of genital infections with canagliflozin than placeboNo change in diabetic ketoacidosis events with canagliflozin, as compared to placeboNo change with canagliflozin, as compared to placeboGreater risk of amputation with canagliflozin, as compared to placebo
      EMPA-REG OUTCOME, 2015
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      No change with empagliflozin, as compared to placeboRenal function maintained with empagliflozin, similar to placeboIncreased rate of genital infection, but not urinary tract infection in the empagliflozin group, as compared to placeboNo change in diabetic ketoacidosis rates with empagliflozin, as compared to placeboNo significant change with empagliflozin, as compared to placeboNo change in bone fracture rates with empagliflozin, as compared to placebo
      Studies on safety concerns during Ramadan fasting
      Beshyah et al., 2019
      • Beshyah A.S.
      • Beshyah S.A.
      The incidence of diabetic ketoacidosis during Ramadan fasting: A 10-year single-centre retrospective study.
      Ramadan fasting was not associated with an increased risk of diabetic ketoacidosis
      Shao et al., 2018
      • Shao Y.
      • Lim G.J.
      • Chua C.L.
      • et al.
      The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes.
      No increased risk of dehydration with SGLT2i during RamadanContinuous use of SGLT2i during Ramadan did not increase the risk of eGFR deteriorationNo events reported with SGLT2i during RamadanSGLT2i did not increase the risk of diabetic ketoacidosis during RamadanContinuous use of SGLT2i during Ramadan did not increase the risk of hypoglycemia
      Hassanein et al., 2017
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      Increased risk of volume depletion with canagliflozin compared to SU during Ramadan, but did not lead to breaking of fast or treatment discontinuationSmall reductions in eGFR from baseline in patients treated with canagliflozin during RamadanNo reported events of genital mycotic infectionsDecreased risk of hypoglycemia with canagliflozin, compared to SU, during Ramadan
      Wan et al., 2016
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      No significantly increased rate of urinary infection with dapagliflozin, compared to SU, during RamadanLower rates of hypoglycemia with dapagliflozin, compared to SU, during Ramadan
      Kamaruddin et al., 2015

      Kamaruddin N, Wan Seman WJ, Kori N, et al. Assessment of dehydration parameters with dapagliflozin in patients with Type 2 diabetes mellitus during Ramadan fasting month (ePoster #757). In: Presented at the 51st annual meeting of the European association for the study of diabetes, Stockholm, Sweden; September 15–18; 2015.

      No increased risk of dehydration with dapagliflozin during Ramadan
      EPIDAIR, 2004
      • Salti I.
      • Bénard E.
      • Detournay B.
      • et al.
      A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: Results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study.
      Severe hyperglycemia with/without ketoacidosis was more common in other months of the year than during RamadanMore frequent events of severe hypoglycemia observed during Ramadan month, as compared to other months
      SGLT2i: Sodium–glucose co-transporter 2 inhibitor; DECLARE-TIMI 58: Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CANVAS: Canagliflozin Cardiovascular Assessment Study; EMPA-REG OUTCOME: Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; CRATOS: Canagliflozin in Ramadan Tolerance Observational Study; EPIDIAR: Epidemiology of Diabetes and Ramadan 1422/2001.

      2.4 Dehydration

      A twofold higher incidence of SGLT2i-associated dehydration was observed in patients aged ≥ 75 years vs. < 75 years; therefore, the use of SGLT2i was cautioned in older patients [
      • Kambara T.
      • Shibata R.
      • Osanai H.
      • et al.
      Use of sodium-glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus.
      ]. However, recent findings from the DAPA-HF trial revealed that both safety and efficacy of dapagliflozin were consistent across all the age groups (22–94 years) of patients studied, even in elderly patients who were on diuretics. These observations reinstated the fact that advanced age should not be a criterion for withholding use of dapagliflozin in elderly patients [
      • Martinez F.A.
      • Serenelli M.
      • Nicolau J.C.
      • et al.
      Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: Insights from DAPA-HF.
      ].
      The use of SGLT2i might also potentially increase the risk of dehydration during long hours of Ramadan fasting in hot climates [
      • Bashier A.
      • Khalifa A.A.
      • Abdelgadir E.I.
      • et al.
      Safety of sodium-glucose cotransporter 2 inhibitors (SGLT2-I) during the month of Ramadan in Muslim patients with type 2 diabetes.
      ]. A lack of difference in volume depletion was observed between the dapagliflozin/empagliflozin and placebo groups in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58), and Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trials [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]. However, in patients who fasted during Ramadan, canagliflozin was found to be associated with a higher number of volume depletion events compared to sulfonylureas, although the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) study supported the use of canagliflozin in these patients since it was generally well-tolerated [
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      ]. On the other hand, no increased risk of dehydration was observed in patients treated with dapagliflozin, who fasted during Ramadan [
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ,

      Kamaruddin N, Wan Seman WJ, Kori N, et al. Assessment of dehydration parameters with dapagliflozin in patients with Type 2 diabetes mellitus during Ramadan fasting month (ePoster #757). In: Presented at the 51st annual meeting of the European association for the study of diabetes, Stockholm, Sweden; September 15–18; 2015.

      ]. Another study demonstrated that the risk of dehydration is not increased in patients on stable SGLT2i therapy, during Ramadan fasting [
      • Shao Y.
      • Lim G.J.
      • Chua C.L.
      • et al.
      The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes.
      ]. These findings do provide some reassurance in general with respect to the use of these agents in Ramadan. However, it is important to remember that these trials did not include elderly patients or those on loop diuretics. Patients on SGLT2i wishing to fast during Ramadan should be advised to increase the intake of fluids in the non-fasting period to minimize dehydration risk [
      • Beshyah S.A.
      • Chatterjee S.
      • Davies M.J.
      Use of SGLT2 inhibitors during Ramadan: A survey of physicians' views and practical guidance.
      ].

      2.5 Effects of SGLT2i on creatinine levels and chronic kidney disease

      Previously, a higher incidence of intravascular volume depletion was observed in older adults (>65 years) with SGLT2i use, especially in individuals with moderate renal impairment, with or without the concomitant use of loop diuretics [
      • Lamos E.M.
      • Hedrington M.
      • Davis S.N.
      An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors.
      ]. However, based on recent evidences on the reno-protective effects of SGLT2i in clinical study outcomes, the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines have strongly recommended the use of SGLT2i in the antihyperglycemic treatment regimen of patients with type 2 diabetes, having CKD and eGFR ≥ 30 mL/min/1.73 m2 [

      Kdigo Clinical Practice Guideline on Diabetes Management in Chronic Kidney Disease. Public review Draft, 2019. Available at: <https://kdigo.org/wp-content/uploads/2018/03/KDIGO-Diabetes-Management-in-CKD_Public-Review.pdf>. Accessed on: 10 February 2020.

      ]. In addition, all the three studies on the safety of SGLT2i use during Ramadan did not mention any significant deterioration of renal function [
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      ,
      • Shao Y.
      • Lim G.J.
      • Chua C.L.
      • et al.
      The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes.
      ,
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ]. However, the studies conducted on SGLT2i during Ramadan fasting included people with normal renal function. Indeed, patients with advanced stages of CKD and diabetes are advised not to fast in the various guidelines mentioned earlier [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ,
      • Al-Arouj M.
      • Bouguerra R.
      • Buse J.
      • et al.
      Recommendations for management of diabetes during Ramadan.
      ,
      • Bajaj H.S.
      • Abouhassan T.
      • Ahsan M.R.
      • et al.
      Diabetes Canada Position Statement for People with Types 1 and 2 Diabetes who Fast During Ramadan.
      ].

      2.6 Genital and urinary tract infections

      Treatment with SGLT2i is associated with urinary tract infections and Candida infections [
      • Baruah M.P.
      • Makkar B.M.
      • Ghatnatti V.B.
      • et al.
      Sodium-glucose co-transporter-2 inhibitor: Benefits beyond glycemic control.
      ]. Studies have demonstrated that mild-to–moderate-intensity genital infections are common during SGLT2i treatment and can be treated with standard antimicrobial medications [
      • Baruah M.P.
      • Makkar B.M.
      • Ghatnatti V.B.
      • et al.
      Sodium-glucose co-transporter-2 inhibitor: Benefits beyond glycemic control.
      ]. Moreover, patients treated with SGLT2i must be educated regarding the maintenance of perineal hygiene to prevent and manage genital tract and urinary tract infections [
      • Kalra S.
      • Baruah M.P.
      • Sahay R.
      Medication counselling with sodium glucose transporter 2 inhibitor therapy.
      ,
      • Unnikrishnan A.G.
      • Kalra S.
      • Purandare V.
      • et al.
      Genital infections with sodium glucose cotransporter-2 inhibitors: Occurrence and management in patients with type 2 diabetes mellitus.
      ].
      The studies conducted on SGLT2i during Ramadan fasting did not show an increase in genito-urinary infections [
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      ,
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ]. One of the factors for a low risk of genito-urinary infections could be safe hygiene practices during Ramadan and/or religious practice of male circumcision in the Islamic culture [
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ,
      • Unnikrishnan A.G.
      • Kalra S.
      • Purandare V.
      • et al.
      Genital infections with sodium glucose cotransporter-2 inhibitors: Occurrence and management in patients with type 2 diabetes mellitus.
      ]. A study reported that among type 2 diabetes patients treated with canagliflozin, genital mycotic infections were more common in uncircumcised men than those who were circumcised (5.7% vs 0.7%) [
      • Nyirjesy P.
      • Sobel J.D.
      • Fung A.
      • et al.
      Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.
      ].

      2.7 Diabetic ketoacidosis and hyperglycemia

      Based on the findings of recent clinical studies, it may be prudent to state that the earlier concern of SGLT2i-induced DKA may not be as common as projected [
      • Shao Y.
      • Lim G.J.
      • Chua C.L.
      • et al.
      The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes.
      ,
      • Salti I.
      • Bénard E.
      • Detournay B.
      • et al.
      A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: Results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study.
      ,
      • Fitchett D.
      A safety update on sodium-glucose co-transporter 2 inhibitors.
      ,
      • Beshyah A.S.
      • Beshyah S.A.
      The incidence of diabetic ketoacidosis during Ramadan fasting: A 10-year single-centre retrospective study.
      ]. Although in the DECLARE study, DKA was found to be more common in the dapagliflozin group compared to placebo (0.3% vs. 0.1%, p = 0.02), the finding was not significant [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ]. The studies conducted on SGLT2i during Ramadan fasting did not show an increase in DKA or ketosis [
      • Shao Y.
      • Lim G.J.
      • Chua C.L.
      • et al.
      The effect of Ramadan fasting and continuing sodium-glucose co-transporter-2 (SGLT2) inhibitor use on ketonemia, blood pressure and renal function in Muslim patients with type 2 diabetes.
      ]. Nevertheless, additional randomized clinical studies are essential for validating the effects of SGLT2i on DKA during fasting.

      2.8 Risk of hypoglycemia

      In general, among patients with a history of recurrent hypoglycemia or severe hypoglycemia within three months prior to Ramadan, or a history of hypoglycemia unawareness, fasting is not recommended. Sodium–glucose co-transporter 2 inhibitor use has been found to be associated with a low risk of hypoglycemia in Ramadan fasting studies when compared to SU [
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ]. Findings from recent studies such as the DAPA-HF trial also report a similar effect of SGLT2i on patients with diabetes, i.e. no effects of SGLT2i on hypoglycemia frequency [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ].

      2.9 Effects of SGLT2i on bone health and amputation

      An increased incidence of bone fractures has been noted in trials with SGLT2i. It has been observed that the risk of fracture increased over time in patients on SGLT2i in the CANVAS study [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ]. In contrast to the CANVAS study, both the EMPA-REG trial and the DECLARE-TIMI 58 trial did not demonstrate any increased risk of amputation or fractures [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Lamos E.M.
      • Hedrington M.
      • Davis S.N.
      An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors.
      ]. Again, recent results from the CREDENCE trial did not show an increased risk of amputation or fracture with canagliflozin [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]. This suggests that the risk of amputation or fractures linked to SGLT2i may not be a class effect, although we need to await for the results of ongoing prospective trials to confirm this further [
      • Matthews D.R.
      • Li Q.
      • Perkovic V.
      • et al.
      Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program.
      ]. At present there are no trials addressing the issue of bone fractures with the use of SGLT2i specifically during Ramadan.
      Peripheral artery disease (PAD), a common comorbidity associated with diabetes, is one of the major causes of lower-extremity amputations. Although PAD-related outcomes remain underrated in published CVOTs, the EMPA-REG OUTCOME trial demonstrated that empagliflozin improved cardiovascular disease (CVD) outcomes in all subgroups of patients studied, including in those with PAD [
      • Chatterjee S.
      • Bandyopadhyay D.
      • Ghosh R.K.
      • et al.
      SGLT-2 Inhibitors and peripheral artery disease: A statistical hoax or reality?.
      ]. A meta-analysis reported that as a class, SGLT2i are not significantly associated with diabetic foot syndrome, although more studies are needed to firmly establish the association between amputation risk and SGLT2i [
      • Li D.
      • Yang J.Y.
      • Wang T.
      • et al.
      Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials.
      ].
      In the context of Ramadan, there is currently no appropriate clinical data on the effects of SGLT2i on bone metabolism, PAD, foot ulcers, and amputation risk in diabetes patients.
      In summary, although the use of SGLT2i had been associated with a few concerns, recent clinical studies have provided convincing results mostly in favor of their use, even during Ramadan. A survey conducted to elicit the opinion of physicians on the use of SGLT2i for the treatment of type 2 diabetes mellitus patients during Ramadan revealed that the majority (70.6%) of physicians considered the use of SGLT2i during Ramadan to be safe and suitable, except in select patients. Most physicians also agreed on the importance of taking extra fluids during the evening after the fast and suggested that SGLT2i should be taken with iftar (evening meal after fast) [
      • Beshyah S.A.
      • Chatterjee S.
      • Davies M.J.
      Use of SGLT2 inhibitors during Ramadan: A survey of physicians' views and practical guidance.
      ]. Therefore, in general, physicians prefer the use of SGLT2i for patients with diabetes during Ramadan, albeit with certain precautions.

      2.10 SGLT2i: initiation/discontinuation, dose alterations, and effect on patient adherence

      In a survey of physicians, initiating SGLT2i therapy immediately prior to Ramadan was not recommended [
      • Beshyah S.A.
      • Chatterjee S.
      • Davies M.J.
      Use of SGLT2 inhibitors during Ramadan: A survey of physicians' views and practical guidance.
      ]. As SGLT2i are associated with fluid loss and diuresis, they must be initiated at least two weeks to one month prior to Ramadan, to allow patients to get acclimatized to the side effects and the unique mode of action of these molecules. Moreover, patients should also be asked to watch out for the symptoms of dehydration [
      • Kelwade J.
      • Sethi B.K.
      • Vaseem A.
      • Nagesh V.S.
      Sodium glucose co transporter 2 inhibitors and Ramadan: Another string to the bow.
      ]. Treatment may need to be discontinued in some patients due to the adverse effects of SGLT2i. However, significant discontinuation of medication was not observed in recent studies on SGLT2i use during Ramadan [
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ]. In fact, patient adherence was high with a few missed fasting days [
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      ]. In another study, a minority of patients were found to break their fast due to symptomatic hypoglycemia [
      • Bashier A.
      • Khalifa A.A.
      • Abdelgadir E.I.
      • et al.
      Safety of sodium-glucose cotransporter 2 inhibitors (SGLT2-I) during the month of Ramadan in Muslim patients with type 2 diabetes.
      ]. However, use of SGLT2i use generally not associated with hypoglycemia, unless there is concomitant use of other agents known to cause hypoglycemia, such as sulfonylureas and insulin [
      • Dandona P.
      • Chaudhuri A.
      Sodium-glucose co-transporter 2 inhibitors for type 2 diabetes mellitus: An overview for the primary care physician.
      ]. These studies revealed that adherence to SGLT2i use improves during Ramadan. Based on the pre-Ramadan assessment, healthcare providers (HCPs) may decide to adjust the dose, type, or timing of medications, to minimize potential risks to the patient [

      International Diabetes Federation. Diabetes and Ramadan: Practical Guidelines. Available at: <https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25.html> Accessed on: 10 February 2020.

      ]. During Ramadan fasting and the pre- and post-fasting periods, SGLT2i should be used after carefully considering the key points summarized in Box 1 [
      • Ali S.
      • Davies M.J.
      • Brady E.M.
      • et al.
      Guidelines for managing diabetes in Ramadan.
      ].
      Important points to consider for using SGLT2i during Ramadan (Adapted from Ali et al., 2016) [10]).
      Assessment before Ramadan:
      Ensuring appropriate selection of patients for SGLT2i use.
      Ensuring absence of contraindications, if any.
      Avoiding use in the elderly, patients on antihypertensive medications, those at risk of dehydration.
      Advising patients on diabetes management during Ramadan.
      Avoiding SGLT2i initiation immediately before Ramadan.
      Monitoring during Ramadan:
      Taking medication with Iftar, i.e. the first evening meal.
      Encouraging adequate fluid intake at night, around extra 500 mL.
      Avoiding excess intake of tea, coffee, or salt.
      Monitoring hydration status, i.e. color and volume of urine.
      Monitoring blood pressure if home monitoring is available.
      Symptoms, if any, to be reported to clinic/surgery.
      Holding medication in case of doubt, and conducting interim diabetes review.
      Reviewing after Ramadan:
      Reviewing patients 4–6 weeks after Ramadan in clinic or surgery.
      Assessing the experiences and outcomes during Ramadan.
      Reviewing the risk/benefit of SGLT2i as a class on an individual basis.
      Reviewing the need for using SGLT2i, and deciding on its continuation or discontinuation.

      3. Efficacy and safety of SGLT2i in diabetes and its associated comorbidities in context of Ramadan fasting

      3.1 Effects of SGLT2i on cardiovascular comorbidities during Ramadan

      The increasing prevalence of diabetes is concurrent with the increase in the prevalence of comorbidities and disabilities associated with diabetes [
      • Harding J.L.
      • Pavkov M.E.
      • Magliano D.L.
      • et al.
      Global trends in diabetes complications: A review of current evidence.
      ]. Heart failure is a widely prevalent life-threatening disease affecting approximately 64 million people worldwide [

      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–59.

      ]. It is expected that one out of five people will develop HF during their lifetime in developed countries [

      One in five people will develop heart failure. ScienceDaily. 2015. Available at: <https://www.sciencedaily.com/releases/2015/05/150505111934.htm>. Accessed on: 10 February 2020.

      ]. The prevalence of diabetes mellitus is high in patients with HF, and in patients with T2DM, the risk of HF is two to five times higher than in the general population [
      • Rosano G.M.
      • Vitale C.
      • Seferovic P.
      Heart failure in patients with diabetes mellitus.
      ]. Although existing diabetes treatments in general efficiently improve glycemic control, their effects on CV outcomes remained unclear. Therefore, in 2008, CV outcome trials (CVOTs) were mandated for all new glucose-lowering therapies by the US FDA [
      • Schernthaner G.
      • Jarvis S.
      • Lotan C.
      • et al.
      Advances in the management of cardiovascular risk for patients with type 2 diabetes: Perspectives from the Academy for Cardiovascular Risk, Outcomes and Safety Studies in Type 2 Diabetes.
      ].
      Three CVOTs have been published on SGLT2i use in diabetic patients, viz. CANVAS, EMPA-REG OUTCOME, and DECLARE-TIMI 58. The efficacy outcomes of these CVOTs included major adverse CV events, i.e. stroke, myocardial infarction, or CV death, and the composite of hospitalization for heart failure (HHF) or CV death [
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ]. A meta-analysis of CVOTs on SGLT2i revealed an overall 11% reduction in the risk of major adverse cardiac events (HR: 0·89 [95% CI 0.83–0.96], p = 0·0014), 16% reduction CV death, and 15% reduction in all-cause death. There was an 11% reduction in the risk of myocardial infarction and a 23% reduction in the risk of HHF with SGLT2i therapy [
      • Zelniker T.A.
      • Wiviott S.D.
      • 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 CREDENCE trial also established a lower risk of CV events with canagliflozin therapy [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]. Overall, CVOTs on SGLT2i have consistently proved their CV benefits in patients with diabetes.
      These CVOTs revealed that the benefits of SGLT2i are most pronounced in reducing HHF in T2DM patients, irrespective of the presence of a history of HF or existing atherosclerotic CV disease [
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ]. In the recent DAPA-HF trial, the risk of worsening HF or death from CV causes in patients with HF and reduced ejection fraction was found to be lower in the dapagliflozin group than placebo group. This observation was irrespective of the presence or absence of diabetes [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]. Although a few studies have evaluated the safety of SGLT2i in diabetic patients during Ramadan, the incidence of HF has not been studied in this context [
      • Bashier A.
      • Khalifa A.A.
      • Abdelgadir E.I.
      • et al.
      Safety of sodium-glucose cotransporter 2 inhibitors (SGLT2-I) during the month of Ramadan in Muslim patients with type 2 diabetes.
      ,
      • Wan Seman W.J.
      • Kori N.
      • Rajoo S.
      • et al.
      Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.
      ,
      • Hassanein M.
      • Echtay A.
      • Hassoun A.
      • et al.
      Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS).
      ]. The consistent CV safety profile of SGLT2i, as obtained in all these recent CVOTs, possibly indicates their CV safety during Ramadan. It must, however, be borne in mind that fasting is not recommended in patients with diabetes and clinically significant HF.

      3.2 Management of diabetes in context of renal function during Ramadan

      Diabetes mellitus is a leading cause of chronic kidney disease (CKD). Changes in glucose metabolism and transport and insulin signaling with the progression of CKD induce insulin resistance. Hence, glycemic control is challenging in patients with kidney failure [
      • Betônico C.C.
      • Titan S.M.
      • Correa-Giannella M.L.
      • et al.
      Management of diabetes mellitus in individuals with chronic kidney disease: Therapeutic perspectives and glycemic control.
      ]. The three trials on SGLT2i have demonstrated that SGLT2i have renoprotective effects and reduce the worsening of end-stage renal disease, renal function, or renal death by 45% (HR 0·55 [95% CI 0.48–0.64], p < 0·0001) [
      • Zelniker T.A.
      • Wiviott S.D.
      • 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.
      ]. In the CREDENCE trial, the risk of the renal composite of end-stage renal disease, a doubling of creatinine level, or death due to renal causes was lower by 34% and the relative risk of end-stage kidney disease by 32% [
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ]. Sodium–glucose co-transporter 2 inhibitors have been demonstrated to delay the progression of renal disease [
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ].
      Based on the outcomes of these trials demonstrating the CV and renal safety of SGLT2i in patients with diabetes, the recent guidelines of both the ADA and the American Association Of Clinical Endocrinologists And American College Of Endocrinology (AACE/ACE) recommend the use of SGLT2i in T2DM patients with established or high ASCVD risk, and/or CKD (with eGFR ≥ 30 mL/min/1.73 m2) [

      American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diab 2020;38(1):10–38.

      ,
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on The Comprehensive Type 2 Diabetes Management Algorithm - 2020 Executive Summary.
      ].
      Several ongoing studies, viz. DAPA-CKD, DIAMOND, and EMPA-KIDNEY, are evaluating the efficacy and safety of SGLT2i in nondiabetic kidney disease patients [
      • Weir M.R.
      Renal effects of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment.
      ]. The results from these studies will prove valuable, since they may orchestrate the evolution of SGLT2i from being anti-hyperglycemic therapeutic agents to cardiorenal protective agents. In this line, the DAPA-HF study found that dapagliflozin preserved renal function in patients with HF and reduced ejection fraction, irrespective of the presence of any diabetic condition [
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ]. Furthermore, due to the overwhelming efficacy and benefits experienced by CKD patients with dapagliflozin in the DAPA-CKD study, an independent Data Monitoring Committee has recommended to stop this trial early [

      Farxiga Phase III DAPA-CKD trial will be stopped early after overwhelming efficacy in patients with chronic kidney disease. AstraZeneca Press Release. Published: 30 March 2020. Available at: Astrazeneca.com/media-centre/press-releases/2020/farxiga-phase-iii-dapa-ckd-trial-will-be-stopped-early-after-overwhelming-efficacy-in-patients-with-chronic-kidney-disease.html. Accessed on: 3 April 2020.

      ].
      Initially, there were no reports on the effects of SGLT2i on diabetic patients during Ramadan. However, a recent study showed that the use of SGLT2i during Ramadan did not cause any significant harmful effects on renal function [
      • Martinez F.A.
      • Serenelli M.
      • Nicolau J.C.
      • et al.
      Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: Insights from DAPA-HF.
      ].

      4. Conclusion

      While earlier studies have reviewed the safety of SGLT2i during Ramadan fasting and evaluated the knowledge, attitude and practices of the physicians in this context [
      • Beshyah S.A.
      Safety of sodium-glucose co-transporter 2 inhibitors during Ramadan fasting: Evidence, perceptions, and guidelines.
      ,
      • Beshyah S.A.
      • Farooqi M.H.
      • Chentli F.
      • et al.
      Medical management of diabetes during Ramadan fasting: Are physicians ready for the job?.
      ], this is the first consensus recommendation on the management of diabetes during Ramadan with SGLT2i for the MEA region, based on the outcomes of recent CVOTs and renal studies.
      In this document, we have attempted to postulate and summarize expert views and opinions on the current management of diabetes during Ramadan with SGLT2i. This document will aid clinicians in the MEA region in decision-making regarding the use of SGLT2i during Ramadan fasting. However, it must be borne in mind that the recommendations made in this consensus document are dynamic and need to be reviewed whenever newer clinical studies and data become available in the context of SGLT2i, especially in relation to Ramadan.
      Summary of Expert Panel Statements
      • People with diabetes should be educated and given support before Ramadan.
      • These educational efforts should be made in alignment with regional or local religious counsellors, diabetes nurse educators, and country-specific authorities.
      • It is important for physicians to start discussing about diabetes management with their patients three to six months prior to Ramadan.
      • The safety results as well as the CV and renal benefits of SGLT2i are reassuring.
      • For the purpose of stabilization, SGLT2i should be initiated at least two weeks to one month prior to Ramadan. SGLT2i are recommended to be administered at the time of evening meal (iftar). However, if the indication for SGLT2i initiation is CV/renal protection, then pre-Ramadan initiation with a low dose would be recommended.
      • Increasing fluid intake during the non-fasting hours is recommended.
      • No dose alterations are required for SGLT2i. If the patient is on a combination of medications, it is prudent to review the dose of medications known to cause hypoglycemia.
      • Raising awareness among physicians about recent guideline changes and the benefits of new antihyperglycemic agents is important.
      • When choosing an anti-hyperglycemic therapy, the impact on HF and renal function must be considered.
      • SGLT2i use in Ramadan should be in accordance with the usual safety and prescribing measures as recommended by each drug SMP. In general terms, SGLT2i should be avoided in the elderly, patients on loop diuretics as well as in those with impaired renal function.

      Funding

      The expert panel meetings were sponsored, and funding for medical writing was provided by AstraZeneca, Middle East Africa.
      Disclosures:

      Acknowledgments

      We would like to thank BioQuest Solutions for providing editorial support and also we would thank Astrazeneca, Middle East Africa for funding the expert panel meeting and medical writing.

      Declaration of Competing Interest

      This review arose from a meeting funded by AZ (all co‐authors,
      thus, acted as honorary consultants to AZ).
      Author Mohamed Hassanein has been speaker for Astra Zeneca, Sanofi, Novonordisk, MSD, BI, Servier, Eli-lilly, Merck and part of Advisory Board for Astra Zeneca, Sanofi, Novonordisk, MSD, BI, Servier. Has received honorarium for attending the Astrazeneca meeting.
      Authors Alaaeldeen Bashier, Hoosen Randeree, Megahed Abouelmagd, Waleed AlBaker, Bachar Afandi, Omar Abu Hijleh, Inass Shaltouth, I Magdy EI-Sharkawy, Selcuk Dagdelen, Samir Assaad Khalil have received honorarium for attending the Astrazeneca meeting.
      Authorship: All authors have contributed equally to the manuscript. All the authors have reviewed the manuscript and have revised for intellectual content wherever suitable. All the authors have reviewed and approved the final draft of the manuscript.

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