Clinical practice points for diabetes management during RAMADAN fast

Accepted Manuscript Title: Clinical practice points for diabetes management during RAMADAN fast Authors: Shaukat Sadikot, K. Jothydev, A.H. Zargar, Jamal Ahmad, S.R. Arvind, Banshi Saboo PII: DOI: Reference:

S1871-4021(17)30193-5 http://dx.doi.org/doi:10.1016/j.dsx.2017.06.003 DSX 801

To appear in:

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Received date: Accepted date:

6-6-2017 6-6-2017

Please cite this article as: Sadikot Shaukat, Jothydev K, Zargar AH, Ahmad Jamal, Arvind SR, Saboo Banshi.Clinical practice points for diabetes management during RAMADAN fast.Diabetes and Metabolic Syndrome: Clinical Research and Reviews http://dx.doi.org/10.1016/j.dsx.2017.06.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Clinical Practice points for Diabetes Management during RAMADAN fast Authors list: 1. Dr Shaukat Sadikot

President at International Diabetes Federation, Executive Board Member - International Atherosclerosis, Association, Consultant at Jaslok Hospital and Research, Centre- Mumbai. 2. Dr. K. Jothydev Department of Diabetology, Jyothydev’s Diabetes and Research Centre (JDC), Trivandrum 3. Dr. A. H. Zargar Past President – Endocrine Society of India, Member Institute Body- AIIMS, New Delhi, Chairman – Independent Ethics Committee – Fortis Hospital. 4. Dr. Jamal Ahmad Professor of Endocrinology & Director, Centre for Diabetes & Endocrinology, Faculty of Medicine, J. N. Medical College Hospital, A.M.U., Aligarh. 5. Dr. S. R. Arvind

Director - DIACON hospital, Diabetes Care and Research Centre, Bengaluru. 6. Dr. Banshi Saboo Chief Diabetologist & Chairman of Diabetes Care & Hormone Clinic, Ahmedabad. Corresponding author: 1. Dr Shaukat Sadikot

President at International Diabetes Federation, Executive Board Member - International Atherosclerosis, Association, Consultant at Jaslok Hospital and Research, Centre- Mumbai.

Abstract Diabetes management during Ramadan is very crucial from the patient perspective as it can present significant risk of hypoglycemia and death when proper care is not taken. Moreover, managing diabetes in fasting Ramadan patients require different mechanisms than the routine diabetes management and pose significant challenge to the health care practitioners. Here we set forth to review the available literature of various clinical trials and studies on different antidiabetic agents in the context of Ramadan. On the basis of available evidence, we suggest that gliclazide is effective and it could be safely recommended in type 2 diabetic patients fasting during Ramadan.

Keywords: Diabetes management; Ramadan fasting; Gliclazide

Conflict of interests: All the authors declare that they have no conflict of interest.

1. Introduction 1.1. Ramadan Ramadan, the ninth lunar month of Muslim calendar, commences upon sighting of the new moon and it typically lasts for about 29 to 30 days.1 Fasting during Ramadan is one of the five pillars (announcement of faith, salaat, zakaat, fasting, and hajj) of Islam and is observed during the time when the Holy Quran was revealed to Muhammad.2 The daily duration of fasting differs as per geographical location and season; in summer and northern latitudes it lasts up to 20 hours, whereas in winter it is observed for much shorter time. During this time, devotees refrain from eating and drinking from dawn to sunset and abstain from smoking, oral medications, and sexual activities.2, 3 During Ramadan period, most of the followers take two meals per day, one at iftar (evening meal after breaking the fast), and another at suhur (meal consumed early in the morning).4 Fasting during Ramadan is believed to be mandatory for every healthy Muslim individual and contravening it without sensible cause is considered as

severe offence.1 However, sick people including patients with diabetes are specifically exempted from the duty of fasting.4 Nonetheless, most of the Muslims, even those who can be exempted, have a passionate desire to participate in this religious ritual during Ramadan.3 1.2. Epidemiology of diabetes during Ramadan fast Diabetes is continuously gaining the status of potential epidemic in the world and in the developing countries. Current estimate reports that there are 415 millions of people with diabetes in the world.3, 5 India has an estimated prevalence rate of about 8.7% and ranked second in the world with approximately 69.2 million diabetic patients.3, 5 The 2011 census of India estimates approximately 172 million Muslims in India, which is growing at the rate of 24.6%.6 Several studies, which included Indian cohorts, reported that around 79% - 94% of Muslims with type 2 diabetes mellitus (T2DM) were undergoing fasting during Ramadan for at least 15 days.7, 8 Taken together, it can be assumed that considerable numbers of Indian Muslims with diabetes, similar to Muslims in rest of the world, follow Ramadan fast in India. 1.3. Physiological changes and risks associated with Ramadan fast Ramadan fasting in Muslim population renders a sudden shift in diet plans, meal timings, sleep and wakefulness patterns. This change of lifestyle carries important consequences for physiology including rhythm and magnitude of fluctuations of various homeostatic and endocrine processes.3 After taking meal the blood glucose level increases, which promotes insulin secretion. Secreted insulin stimulates the storage of glucose as glycogen in liver and muscle. Several hours after meal or fasting, the plasma glucose level decreases and insulin secretion falls down. Subsequently, the counter balancing hormones such as glucagon and catecholamines rise and induce the breakdown of glycogen to glucose. Simultaneously, a process called gluconeogenesis is also amplified. Prolonged fasting for more than a few hours deplete

glycogen stores, which together with low circulating insulin stimulate energy production from fatty acid in adipocytes. Ketones produced by fatty acid oxidation serve as energy source for liver, adipose tissues, kidney, skeletal and cardiac muscles. This process spares glucose for uninterrupted use by brain and erythrocytes during tenure of prolonged fasting. In healthy individuals, as explained above, there is a subtle balance between circulating insulin and counter regulatory hormones, which keep glucose levels in physiological range. However, in patients with diabetes, this balance is distressed. In addition to underlying pathophysiology of both type 1 and type 2 diabetes, pharmacological agents used to control the disease further perturb the homeostasis.4, 9 In agreement with above facts, alteration in diet pattern, meal timings, changes in timing and doses of medication, and physical activity during Ramadan fast generate various risks in patients with diabetes. Complications like hyperglycemia, hypoglycemia, 4,

7, 8, 10

dehydration, diabetic ketoacidosis (DKA) (Almalki MH et al. 2016, Rathor MY et al. 2014),1, 9

and microvascular and macrovascular problems may create major challenges in diabetes

patients during the fasting period.3 Patients with type 1 diabetes mellitus (T1DM) and T2DM may suffer similar perturbations in response to a prolonged fast; however, ketoacidosis is more common in T1DM patients.1, 9 Moreover, the severity of hyperglycemia also depends on the extent of insulin resistance and/or deficiency in T2DM patients. 1.4. Current clinical practice guidelines for the management of diabetes during Ramadan The first American Diabetes Association (ADA) guidelines on the management of diabetes during Ramadan fasting was published in 2005, which was updated in 2010. They classified patients into four risk categories: very high, high, moderate, and low risk and prohibited very high risk and high risk category patients from fasting.4, 11 Similarly South Asian Consensus Guideline was published in 2012 and highlighted the use of pharmacotherapy in the

management of diabetes during Ramadan. The guideline also stratified patients according to the risks and suggested precaution measures and management plan for the diabetes patients who are on fasting.12 International Group for Diabetes and Ramadan (IGDR) recommendations were published in 2015 with a goal of updating the lifestyle modifications and usage of newer pharmacological agents in the treatment of diabetes during Ramadan fast.13 In addition to this, International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance recently formulated practice guidelines for the management of diabetes during Ramadan fast.3 1.5. Rationale for this practice recommendation Ramadan fast is a ubiquitous religio-cultural practice that is found in varying forms across the world including India. It is evident from the above reports that India has good number of Muslim population, which is projected to increase in the coming years, and majority of Indian Muslims observe fasting during Ramadan, the prevalence of diabetes is on a rise in Indian population. Furthermore, fasting during Ramadan is associated with multifactorial risks in diabetes patients. Collective analysis of these aspects urges the development of clinical practice guidelines for diabetes management during Ramadan fasting in India. This review highlights the evidence based management options for diabetes control by using various pharmacological agents. 2. Diabetes management during Ramadan 2.1. Who should undergo fast or who should not? Patients should be categorized whether or not to go for fasting with respect to diabetes associated morbidity and mortality, and safety or tolerability of medications. An international consensus meeting at Morocco concluded that patients with T1DM, unstable T2DM, and diabetes patients with complications, pregnant women with diabetes, and old age people with

diabetes should not undergo fasting. However, T2DM patients with stable disease with or without oral-antihyperglycemic agents (OADs) could observe the ritual during Ramadan.14, 15 IDF suggested that very high and high risk category patients could refrain from fasting; however, many of these patients will choose to do so and this must be respected.3 Risk stratification of patients according to their comorbidity and patients who can abstain from fasting during Ramadan has been depicted in Table 1. 2.2. When to break the fast? Diabetes patients who are on fasting should end their fast if the blood glucose level decreases to <60 mg/dL (hypoglycemia) or increases to >300 mg/dL (hyperglycemia), or when symptoms of dehydration or DKA are observed. Fasting should also be broken, especially by those patients taking insulin, sulfonylurea drugs or meglitinides at predawn, when the blood glucose levels in the first few hours after the start of the fast fall below 70mg/dL.4 Patients and their family members must be well educated about the signs, symptoms, and evaluation of hypoand hyper-glycemia; they should be encouraged to go for quick blood glucose estimation. 3 Moreover, after breaking the fast due to hypoglycaemia, patients should consume a little amount of a fast-acting carbohydrate diet.3, 16 2.3. Pre-Ramadan education and medical assessment Pre-Ramadan diabetes education enables the patients to make informed decisions and effectively manage themselves during the fasting. A structured educational programme should be devised for the patients and their families, which gives information on risk quantification, physical activity, glucose monitoring, diet, hypoglycemia, dosage and timing of medications, and identification of the symptoms of complications.3, 17 All diabetic patients with a desire to go for fasting should receive proper diabetes counselling at least 1-2 months prior to Ramadan.13 The READ programme revealed that patients who received structured education

programme had experienced significantly less weight gain (p-value <0.001) and hypoglycemic episodes (p-value <0.001) compared to those who were not educated on the diabetes management.18 Further, a systematic diabetes education with structured patient counselling reduces the risk of acute complications during Ramadan fast.19 Pre-medical assessment during patient counselling plays a vital role in deciding the patient’s eligibility for fasting during Ramadan and also helps in excluding further unavoidable risks and complications. This assessment includes measurements of glycemic levels (haemoglobin and HbA1c), estimation of blood pressure and lipids, and a total annual review along with specific advice on potential harms of fasting

15

. Furthermore, following points

should be discussed with the patients who wish to go for fasting during Ramadan. 9. 17 

Patients should monitor their glucose levels several times daily as skin puncturing with glucose monitoring devices does not affect the fasting.



Insulin injections during Ramadan are permitted, as it offers no food value



All OADs during Ramadan can be used with strict glucose monitoring



Patients should consume fluid profusely, and the iftar meal should be taken as late as possible to delay digestion and absorption.



All patients should maintain normal levels of activity and get enough sleep.



Patient should break their fast immediately in the occurrence of acute complications like hypoglycemia or hyperglycemia.

2.4. Nutrition Alteration in dietary pattern, meal timings, and meal composition during Ramadan fasting generates various health consequences in the patients with diabetes. The Epidemiology of Diabetes and Ramadan (EPIDIAR) study reported that around 15-30% of the diabetes patients either gain or lose their body weight during Ramadan period.8 Therefore, the nutrition plan

should be highly individualized according to the risk of the patient and should provide adequate energy by maintaining adequate glycemic level without any complications. Consuming complex carbohydrates like whole grain, potato, berries, citrus fruits, watermelon, apple, nuts, and legumes at the suhur, and simple carbohydrates like bread, cereals, rice, mango, pasta, and artificial syrups at the iftar may be more appropriate.4 It is advised to avoid one big meal during the non-fasting period; rather it should be divided into two to three smaller meals to prevent post-meal hyperglycemia.9 Sufficient quantity of water and non-sweetened beverages should be taken between two meals to avoid dehydration.3 A caloric target of 1800 kcal/day for male and 1200-1500 kcal/day for female is optimum for reduction of body weight in T2DM patients undergoing fasting. Further, the total caloric intake should be divided as suhur (30-40%), iftar (40-50%), and snacks between meals (10-20%) to avoid hypo- and hyper-glycemia.3 Figure 1 represents an exemplary food plate for the diabetes patients during Ramadan fast. This nutrition plan guides the diabetes patients for estimating their daily caloric target (1500-2200 kcal) which may further help in maintaining sufficient blood glucose level by eliminating various risks and complications. 2.5. Life-style modifications Lifestyle therapy alone may impose less risk with fasting in patients with well-controlled T2DM. However, there is still a potential risk for occurrence of postprandial hyperglycemia if patients indulge in overeating.17, 18 Additionally, lifestyle changes and eating patterns during Ramadan predispose patients with diabetes to an increased risk of hypoglycaemia during the daytime and hyperglycaemia at night.3 However, improved life style management plays a major role in reducing complications of diabetes during fasting.18, 19 Physical activity is a good option for patients to lose body weight especially in the month of Ramadan; however excessive and aggressive physical activity should be avoided.20, 21 Exercise should be done for 30 minutes before iftar or 2-3 hours after iftar in an air conditioned environment. Any type of physical

activity should be immediately stopped in case of dizziness, nausea, and difficulty in breathing or chest pain.22 3. Pharmacological management of diabetes during Ramadan fasting 3.1. Management of type 1 diabetes patients The T1DM patient willing to observe Ramadan fasting are considered as very high-risk patients. Further, the risk replicates with patients unable/unwilling to monitor blood glucose level, uncontrolled/poorly-controlled diabetes, no access to medical care, uneducated and unawareness to hypoglycemic events and requiring recurrent hospitalizations.4 In the EPIDIAR study, more than 40% of T1DM patients were observing fasting at least for 15 days. 8 Intensive glycemic control with multiple daily insulin injections or insulin pump is the current standard of treatment for the patients with T1DM (Pathan et al. 2012). The South Asian Consensus Guideline suggests that patient should be managed with once-or-twice daily injections of intermediate or long-acting insulin along with pre-meal rapid-acting insulin during Ramadan.12 In addition to the control measures, IDF suggests that all T1DM patients should be in strict glycemic monitoring throughout the fasting period.3 Insulin dose adjustments during Ramadan are summarized in table 2. 3.2. Management of type 2 diabetes patients Patients with T2DM managed by diet and physical exercise alone can undergo fasting without any significant risks; however, those on some of the OADs could be at risk during Ramadan fasting. Therefore, the pharmacological therapy should be individualised as per patient’s medical history, glycemic goals, education, and complications. Details of dose adjustments for different OADs during Ramadan are given in table 2. It should be emphasized that the dose of drugs should be adjusted to pre-Ramadan dose after Ramadan.

3.2.1. Patients on oral hypoglycemic agents 3.2.2.1. Metformin Due to minimal incidences of hypoglycemia, metformin can be used safely in patients with diabetes during fasting. However, the evidence of metformin use in T2DM patients during Ramadan fasting is limited to non-randomized studies. Further, patients who are not taking once daily formulation requires some dose adjustments to avoid complications. 3.2.2.2. Sulphonylureas Sulfonylureas have emerged as the most commonly prescribed drugs after metformin for the management of T2DM. The quick glycemic response, time-tested experience, and low cost make sulfonylureas popular and position them in second place in the T2DM management, particularly in south-Asia.23,

24

Extensive evidence is available on efficacy and safety of

sulfonylureas (gliclazide) during Ramadan fasting, a summary of which is described in Table 3. Glucose-independent insulin secretion by sulfonylureas may raise the risk of hypoglycaemia compared with other OADs that shows apprehension about their use during Ramadan. Nevertheless, the incidence of hypoglycemia varies across drugs within this class. A Cochrane systematic review and meta-analysis reported that modern sulfonylureas (gliclazide and glimepiride) do not significantly affect all-cause mortality (RR: 0.98, 95% CI: 0.61–1.58) or cardiovascular mortality (RR: 1.47, 95% CI: 0.54–4.01) compared to metformin in patients with T2DM.25 Further, among all sulfonylureas, gliclazide XR (extended release) was associated with a lower risk of all-cause and cardiovascular-related mortality in T2DM patients.26 Moreover, a recent systematic review of RCTs reported that gliclazide or DPP4 inhibitors are associated with low risk of hypoglycemia during Ramadan fasting. 27 The STEADFAST study comparing vildagliptin or gliclazide as an add-on to metformin reported

no statistically significant difference in hypoglycemia episodes (P=0.173) and body weight reduction (P=0.423) between the treatment groups during Ramadan fast.28 It can be inferred from the above evidence that taking advantage of lower hypoglycemic episodes and reduced risk of CV related complications together with low cost, gliclazide can be effectively and safely recommended in Indian patients with T2DM during Ramadan fasting.23, 29 It is also recommended to avoid glibenclamide and prefer new sulfonylureas such as gliclazide and glimepiride during Ramadan fasting.3 The treatment need to be individualized with proper dose adjustments in a clinical setting.3

3.2.2.3. Short-acting insulin secretagogues Owing to their short duration of action, agents like repaglinide and nateglinide may be taken before iftar and suhur. Anwar et al. reported no significant difference in terms of hypoglycemia between repaglinide and glimepiride; however, due to the longer duration of action, glimepiride might be advantageous during the long hour fasting period in Ramadan.30 Nateglinide has not been studied during Ramadan; nevertheless, due to its shorter duration and faster onset of action compared to repaglinide, this drug can also be safely used during Ramadan fasting. 4

3.2.2.4. Thiazolidinediones Insulin sensitizers like thiazolidinediones (TZD) are associated with lower hypoglycemic complications compared to insulin secretagogues. However, when used concomitantly, they may increase the hypoglycemic effect of sulfonylureas, glinides, and insulin. Evidence on use

during Ramadan is limited. Vasan et al. reported that pioglitazone significantly improved glycemic control (P=0.01) with no difference in hypoglycemic events (P=0.21) compared to placebo, but weight gain (P=0.001) from baseline and ankle edema (P=0.0002) was the most frequent adverse effect noted in the pioglitazone group.31 Factors like weight gain and an anecdotal increase of appetite have made TZDs unsuitable for replacement with other OADs during Ramadan fasting.4 3.2.2.5. Dipeptidyl peptidase-4 inhibitors Dipeptidyl peptidase-4 (DPP-4) inhibitors work by increasing insulin secretion in a glucosedependent manner; therefore, they are not associated with the risk of hypoglycemia. However, they may amplify the hypoglycemic effect of sulfonylureas when used in combination. 9 Sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin are commercially available DPP4 inhibitors, of which the efficacy and safety of later three are yet to be evaluated during Ramadan fast. A recent systematic review and network meta-analysis reported that DPP-4 inhibitors were associated with lower incidence of hypoglycemia during Ramadan as compared to sulfonylureas.32 A multicenter randomized study including 765 Indian T2DM patients during Ramadan period reported that the risk of hypoglycemia (≥1 episode) was lower with sitagliptin compared to sulfonylureas (4.1% vs. 7.7%); however, the study was limited by overestimating the hypoglycemic events. Patients from both the group had neither discontinued treatment nor required medical assistance during the study period.33 Of a total four RCTs

28, 33, 34, 35

investigating the impact of switching from sulfonylureas to either vildagliptin or sitagliptin prior to Ramadan compared with continuing on sulfonylureas, two trials reported significant reduction in the risk of hypoglycemia with DPP-4 inhibitors compared to sulfonylureas.33, 34 However, the incidence of hypoglycemia was similar to gliclazide. The observational evidence on DPP-4 inhibitors, including the VECTOR, VERDI, and VIRTUE studies supports efficacy

and safety of vildagliptin during Ramadan fast.36, 37, 38 In summary, vildagliptin, and sitagliptin are safe and effective options to offer in the treatment of T2DM during Ramadan fast. 3.2.2.6. Sodium-glucose cotransporter-2 inhibitors The Sodium-glucose cotransporter-2 (SGLT-2) inhibitors display good glycemic control, improve weight loss, and exhibit low risk of hypoglycemia. The available SGLT-2 inhibitors are dapagliflozin, canagliflozin, and empagliflozin. Volume contraction, genitourinary infections, the risk of dehydration and DKA represent a concern for patients with prolonged fasting in warm or hot climates.3, 13 The evidence on the safety of this class of agents in Ramadan is limited to only one study (table 3). Although SGLT-2 inhibitors are recommended during Ramadan, a category of patients who are at high risk of developing complications such as elderly patients, patients with renal impairment, hypotensive individuals, and those at risk of dehydration or taking diuretics should not be treated with these agents.3

3.2.2.7. Glucagon-like peptide-1 receptor agonists Owing to the glucose-dependent mechanism of action, glucagon-like peptide-1 (GLP-1) receptor agonists have a low risk of hypoglycemia; nevertheless, they can enhance the hypoglycemic effect of other OADs when used in combination therapy.4 The Treat 4 Ramadan trial did not find statistically significant difference (P = 0.06) in terms of weight gain, and severe hypoglycemia between liraglutide and sulfonylureas, and reported both drugs were well tolerated without any complications in patients with T2DM during Ramadan.39 The LIRARamadan trial did not report any significant difference between liraglutide and sulfonylureas in terms of severe hypoglycemia and adverse effects (23.7% VS 20.9%); although, weight loss (P = 0.0091) and HbA1c reduction (p < 0.0001) were significant in liraglutide group.40 Studies

of lixisenatide, dulaglutide and albiglutide during Ramadan are lacking and that of exenatide is limited to only one study. Considering above evidence, liraglutide may be effective in the management of T2DM patients during Ramadan as an add-on to metformin. 3.2.2.8. Alpha-glucosidase inhibitors Alpha-glucosidase inhibitors (AGIs) such as acarbose, miglitol, and voglibose are usually prescribed when glycemic control is not achieved with diet and physical activity alone. However, owing to their ineffectiveness as monotherapy and frequent gastrointestinal side effects, these drugs have little use in the T2DM management.4, 9 There are no RCTs for their use in the treatment of T2DM during Ramadan. 3.2.2. Patients with insulin Use of insulin analogs during prolonged fasting carries the risk of various complications in T2DM patients, although the risk of hypoglycemia is lower compared to T1DM patients.4 Even though the data pertaining to the optimal insulin type or regimen for patients with T2DM during Ramadan is limited, individualized insulin treatment may be safe during Ramadan fast.3 Rapidacting insulin analogs are associated with lower incidence of hypoglycemia and minimal postprandial hyperglycemia.41, 42 Insulin glargine is safe to use during Ramadan period as it was not found to associate with a significant increase in hypoglycemia when compared with non-fasting individuals or when compared with those taking other OADs.43 Basal and premix insulins were non-inferior to the standard of care in patients with T2DM and were associated with less adverse events during Ramadan fast.44 Reznik et al found that insulin pump could be a safe and valuable treatment option for patients with poor glycemic control even after using multiple daily injections of insulin.45 Data regarding the use of insulin pump in patients with T2DM during Ramadan fast are limited. Nonetheless, patients with T1DM can fast safely during Ramadan using insulin pump.3 Insulin therapy can be used safely during Ramadan with

some dose adjustment depending on meal timings. The details of dose adjustments during Ramadan fast have been depicted in table 2. 3.2.3. Ramadan and economic implications of OADs Medication cost plays a major role in the management of diabetes especially in patients with poor economic background who have limited access to medical insurance.23 A cohort study comprising 254,973 patients reported that metformin ($32.40) and sulfonylureas ($30.60) are associated with fewer co-payments during 6 months of medication initiation in contrast to AGIs, TZDs, meglitinides, or DPP-4 inhibitors ($127.90).46 In the developing countries like India, sulfonylureas are the most prescribed second-line agents (76.28%) after metformin in the management of T2DM.47 Moreover, sulfonylureas are associated with a significantly lower cost per quality-adjusted-life-years (QALYs) and result in the longest time to insulin dependence.48 In summary, lower treatment cost without compromising the glycemic efficacy and tolerability has made sulfonylureas the prime choice of treatment in the South Asian populations during Ramadan fast.23 4. Special populations 4.1. Elderly Elderly people do not refrain from Ramadan fasting usually. These people, particularly those with long-standing diabetes, may present with multiple concomitant diseases that have an adverse impact on the safety of fasting.49 The IDF recommends that older people who have enjoyed fasting during Ramadan for many years should not be categorised as high risk based only on a specific age but rather should be based on health status and social circumstances. 3 The majority of clinical practice guidelines have classified elderly patients with illness into a

very high-risk category and suggested to abstain from fasting. Medications like SGLT-2 inhibitors should not be used in elder diabetic patients due to the risk of dehydration and volume contraction.13 4.2. Pregnancy It is advised that pregnant and lactating women should not follow fasting, which otherwise may put their own health or the health of their offspring in danger.50 The ADA and IDF have categorized pregnancy into a very high-risk category and have advised pregnant women to abstain from Ramadan fasting. However, evidence suggests that a large number (70–90%) of pregnant women do observe fast during Ramadan.51 There are two categories of pregnant patients: one with pre-existing diabetes and the other who suffer from gestational diabetes. The management of pregnant patients during Ramadan includes providing an appropriate preRamadan assessment and education to ensure that the required diet and insulin dose adjustment are in place. It is worthy to note that pre-existing diabetes affects women throughout the course of pregnancy, while gestational diabetes appears either in the second or third trimester of pregnancy. These patients are treated with the drugs that do not exhibit the risk of maternal or fetal complications. Most of the patients are treated with insulin, metformin, or glibenclamide, which carry a greater risk of hypoglycemia. Hence, these patients should be monitored more frequently as compared to other risk groups.9 5. Conclusion Management of diabetes in Indian patients during Ramadan fast still presents a significant challenge for health care practitioners and physicians. Specifically, patients with T1DM position themselves at very high risk due to consequences of hypo- and hyper-glycemia during the fasting period. Most of the OADs produce hypoglycemia in T2DM patients which subsequently impose the need for modifications/management of the regimen during the fasting

period. Very few RCTs have reported the effectiveness of OADs during fasting in the management of T2DM, this demands further trials in a large number of diabetes patients during Ramadan to widen the current knowledge. Nonetheless, newer agents like gliclazide, glimepiride, and DPP-4 inhibitors have been shown to be efficacious and safe in achieving the glycemic targets in diabetes patients during Ramadan fast. From the available evidence, it can be inferred that lower hypoglycemic episodes, reduced risk of CV related complications and being a cost-effective treatment, gliclazide can be effectively and safely recommended in Indian patients with T2DM during Ramadan fast.

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Figure 1. Example of food plate for Ramadan. The plate can be adapted as per individual daily caloric intake. The percentage of carbohydrate, fat and proteins can be adjusted to meet the cultural setting and food preference of each individual

Table 1: Risk Stratification of patients with diabetes during Ramadan fast Very high risk o Severe hypoglycemia /

High risk o Moderate hypoglycemia

Moderate risk o Well controlled

Low risk o Well controlled

ketoacidosis / hyperosmolar

(Average blood glucose

patients (HbA1c

patients (HbA1c

hyperglycemic coma within

150-300mg/dL)

<7.5%) treated

<7%) treated

last 3 months prior to

o Renal insufficiency

with short-acting

with diet alone,

Ramadan

o People living alone that

insulin

metformin, or a

are treated with multiple

secretagogues and

thiazolidinedione

insulin injections

modern

who are

sulphonylureas

otherwise

o History of recurrent hypoglycemia

o Hypoglycemia unawareness o Old age with ill health o Sustained poor glycemic control

o Patients with macro and microvascular

o Patients on dialysis

complications that

o Patients who perform

present additional risk

intense physical labor

factors

o Acute illness o Gestational diabetes mellitus treated with insulin o Pregnancy o Type 1 diabetes The following patients should refrain from fasting  Pregnancy and lactation  Type 1 diabetes  Acute peptic ulcer  Cancer  Severe bronchial asthma, pulmonary tuberculosis  Overt cardiovascular diseases- recent MI, sustained angina  Hepatic dysfunction Adapted from: South Asian Consensus Guideline, ADA 2005, IDF 2016, and IGDR 2015

healthy

Table 2. Dose adjustment/modifications for the management of type 2 diabetes during Ramadan fast Anti-diabetic agents Metformin

Current regimen

Recommended dose modification during Ramadan

 Take at Iftar  Take at iftar and suhur  Take 2/3 of the total daily dose at the iftar and the other 1/3 at the suhur Once daily Sulfonylureas*  Take at iftar Twice daily  Take 1/2 of usual evening dose with the suhur and the usual morning dose with the Iftar Glinides  The daily dose may be ↓ or divided to 2 doses according to meal size and should be taken at iftar and suhur TZD  No dose adjustments is required DPP-4 inhibitors  No dose adjustments required Acarbose  No dose adjustments is required SGLT-2  No dose adjustment is required and the dose be taken with iftar inhibitors† GLP-1 receptor  The dose should be titrated 6 weeks prior to Ramadan and no dose adjustment is required agonists AGIs  No dose modification is required Once-daily Long-acting  ↓ dose by 15–30% and take at iftar insulin Twice daily  Take usual morning dose at iftar  ↓ evening dose by 50% and take at suhur Short-acting  Take normal dose at iftar and lunch-time dose at dinner  ↓ suhur dose by 50% insulin Once daily Premixed  Take normal dose at iftar insulin Twice daily  Take 1/2 of usual evening dose with the suhur and the usual morning dose with the iftar Thrice Daily  Omit afternoon dose and adjust iftar and suhur doses  Carry out dose titration every 3 days Basal rate Insulin pump  ↓ dose by 20–40% in the last 3–4 hours of fasting  ↑ dose by 0–30% early after iftar Bolus rate  Normal carbohydrate counting and insulin sensitivity principles apply Once daily Twice daily Thrice daily

AGIs, alpha-glucosidase inhibitors; DPP-4, dipeptidyl peptidase-4; SGLT-2, sodium-glucose co-transporter-2; TZD, thiazolidinedione *Gliclazide and glimepiride should be preferred among all other sulphonylureas † Elderly patients, patients with renal impairment, hypotensive individuals, those at risk of dehydration or those taking diuretics should not be treated with SGLT2 inhibitors. Adapted from: South Asian Consensus Guideline, ADA 2005, IDF 2016, and IGDR 2015

Table 3: Studies investigating efficacy and safety of sulphonylureas (gliclazide) in the management of diabetes during Ramadan fast Author et N Intervention al. Randomized clinical trials

Outcomes / conclusion

 Similar ↓ in fructosamine levels were observed f (liraglutide, −12.8 μmol/L; sulphonylurea, −16.4 μ  No severe hypoglycemic episodes were reported  More subjects in the glibenclamide stratum (14 episodes than in the glimepiride/gliclazide/glipizid

Azar S T et al. 2016

343

Liraglutide vs sulphonylureas (gliclazide, glimepiride, glipizide, glibenclamide): outcomes

Hassanein M 2014

557

Vildagliptin (A) vs gliclazide  Confirmed hypoglycemia (A vs B): 3.0% vs 7.0% (B) + metformin: Hypoglycemic  Adjusted mean change pre- to post-Ramadan in H events vs −0.03% ± 0.04% (P=0.165).  Adjusted mean ↓weight: −1.1±0.2 kg (P=0.987) fo  No significant change in any parameter found in

Malha LP 2014

69

Vildagliptin vs sulphonylureas (Glimepiride/ gliclazide): hypoglycemia event

Brady EM et al. 2014

99

Liraglutide (A) vs sulphonylureas (B) (gliclazide, glipizide or glibenclamide):

Aravind S R 2012

765

Sitagliptin (A) vs sulfonylureas (B) (Glimepiride/ gliclazide/ glibenclamide) ± metformin: overall incidence of symptomatic hypoglycemia

 Hypoglycemic events in Indian patients (A vs B) (Gliclazide
Al Sifri S 2011

1066

Sitagliptin vs sulphonylureas (Glimepiride/ gliclazide/ glibenclamide): overall incidence of symptomatic hypoglycemia

 Risk of symptomatic hypoglycemia: Sitagliptin, 6 glimepiride, 12.4%; glibenclamide, 19.7%  No reported events that required medical assistanc during Ramadan  The incidence of hypoglycemia was lower with g sulphonylureas and similar to that observed with s

Observational studies Vildagliptin vs sulphonylureas Shete A et 97 (Glimepiride/ gliclazide/ al. 2013 glibenclamide/ glipizide)

Aravind S R 2011

1378

Glimepiride/ gliclazide/ glibenclamide ± metformin: overall incidence of symptomatic hypoglycemia

 HbA1c from baseline to the last visit was similar  Hypoglycemic events was not statistically signifi groups  Vildagliptin may be a better agent than sulphonylu  There were no episodes of severe hypoglycemia recorded episodes of blood glucose ≤3.9 mmol/L:  Change in HbA1c 3 weeks post-Ramadan: A>B;↓  Body weight 3 weeks post-Ramadan: A>B; ↓2.23

 Hypoglycemic episodes were reported in low freq and the sulfonylurea groups [0 vs 2 patients, respe  HbA1c ↓by -0.43% in the vildagliptin group (P = sulfonylurea group (P = 0.958)  Both treatment groups were well tolerated during  Symptomatic hypoglycemia drug wise: glibenclam gliclazide, 14.0%  Symptomatic hypoglycemia country wise: Israel, 4 India, 13%; Saudi Arabia, 10%

Zargar AH 20102

136

Gliclazide MR 60 mg monotherapy, switched to evening administration of the same dose during Ramadan

Sari et al, 2004

40

Repaglinide vs sulphonylureas (glimepiride & gliclazide): outcomes

 ↓Mean FPG by 0.01 mmol/l (P = 0.3) with evenin fast.  Hypoglycemic episodes: before Ramadan, 3.7%, ; 1.5%  Gliclazide evening administration safely mainta fast  Only 1 hypoglycemic event reported in glimepirid  ↓triglyceride levels from BL: Repaglinide (p=0.0  ↑ HDL-cholesterol from BL: Repaglinide (p=0.0

Table 4. Proposed practice points for the management of diabetes during Ramadan fast Key points:  Patient with diabetes necessitates special attention during fasting in Ramadan period.  Patients along with their families should undergo a structured pre-Ramadan counselling with appropriate medical education.  Patients should follow a proper nutrition plan to avoid complications during Ramadan fast.  Patients stratified as very high risk and high risk category should not undergo fasting during Ramadan, however if they do so, it is respected and necessitates a strict medical supervision and regular monitoring of the glycemic levels and complications.  Patients with type 2 diabetes can fast without any severe complications; however they may require some dose adjustment/ modifications to their on-going treatment regimen.  Incretin based therapies and thiazolidinediones are effective in the management of diabetes during Ramadan fast. Nevertheless, their capability to enhance hypoglycemia episodes when used in combination with other OADs and high cost limits their applicability.  Sodium-glucose cotransporter-2 inhibitors should be used cautiously due to their volume of contraction and dehydration effects.  Sulphonylureas are recommended options as second-line agent after metformin in the treatment of diabetes due to their extended efficacy and low cost, which may be suitable for Indian patients. Owing to their benefits such as lower hypoglycemic episodes and longer duration of action, modern sulphonylureas like gliclazide and glimepiride might be more effective in the management of T2DM during fasting period. Taking into account reduced risk of CV related complications and being a cost-effective treatment, gliclazide may be considered as a safe and effective option in patients observing Ramadan fast.