Carlton citadel Hotel , Aleppo, July 20th Diabetes & Ramadan Dr. Nizar Albache Head of Diabetes Research Unit, Aleppo University President of Syrian Endocrine Society Carlton citadel Hotel , Aleppo, July 20th

Diabetes & Ramadan Why Muslims should fast ? When Muslims should fast ? What are the metabolic changes during fasting and their consequences on diabetes control ? Who should not fast ( exempted) ? Religious recommendations Medical recommendations What are the diet advices ? What are the therapeutic changes or recommendations ?

Diabetic Patients in the Muslim Countries Muslims: 1.1-1.5 Billion around the world The prevalence of type 2 diabetes in the Muslim World is very high ( 10-20 %) What percentage of diabetic patients actually fast ? 20 %

T2 Diabetes: Insulin resistance + insulinopenia Glycemia Insulin secretion Time No diabetes Pre- diabetes Type 2 Diabetes

Decline of ß-cells function determines the progressive nature of T2DM 100 ? Time of diagnostic 80 60 ß-cell function (%of normal by HOMA) Pancreatic function = 50% of normal 40 20 -12 -10 -8 -6 -4 -2 2 4 6 Time (years) HOMA=homeostasis model assessment. UKPDS Group. Diabetes 1995;44:1249-58. Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21-5.

ADA/EASD Consensus Guidelines Treatment Algorithm, 2006 Diagnosis Step 1 Lifestyle intervention + Metformin HbA1c  7% Step 2 Add basal insulin (Most effective) Add sulfonylurea (Least expensive) Add glitazone (No hypoglycemia) Additional medications: insulin, sulfonylureas or TZDs, on the top of metformin Nathan DM, et al. Diabetes Care 2006;29:8.

ADA/EASD guidelines recommend use of basal insulin as early as the second step in type 2 diabetes management Tier 1: well-validated core therapies Lifestyle + Metformin plus Basal insulin Lifestyle + Metformin plus Intensive insulin At diagnosis: Lifestyle + Metformin Lifestyle + Metformin plus Sulfonylureaa Check HbA1C every 3 months until <7%. Change treatment if HbA1C is ≥7% STEP 1 STEP 2 STEP 3 Tier 2: Less well validated therapies Lifestyle + Metformin plus Pioglitazone No hypoglycaemia Oedema/CHF Bone loss The ADA and EASD issued this consensus statement in 2008 as an algorithm for the management of hyperglycemia in patients with T2D. T2D is a progressive disease. Therefore, when required, treatment can be intensified by adding a further agent to the existing treatment regimen. The guidelines state that the goal of treatment should be to reduce HbA1c as close to the healthy range as possible (<6.0%) or, at the very least, to <7.0%. When lifestyle modification and treatment with metformin fails to achieve HbA1c levels <7.0%, the addition of basal insulin should be considered (Step 2). An alternative option is the addition of basal insulin at step 3 instead of a third OHA. Initiation orintensification of insulin is the preferred option at this stage, because the addition of a third OHA is no more effective than insulin and is more costly. Intensification of insulin therapy should be achieved by adding prandial insulin injections at selected meals to decrease postprandial BG levels. The ADA/EASD recognize that the HbA1c target of 7.0% is not practical for some patients and recommend that the potential risks and benefits of intensified treatment are assessed for every patient. Lifestyle + Metformin plus Pioglitazone plus Sulfonylureaa Lifestyle + metformin plus GLP-1 agonistb No hypoglycaemia Weight loss Nausea/vomiting Lifestyle + Metformin plus Basal insulin Sulfonylureas other than Glybenclamide or chlorpropamide Insufficient clinical safety data; CHF, congestive heart failure Nathan DM, et al. Diabetes Care 2008;31:1-12.

Target not reached at 6 months HbA1c >7% Types 2 Diabetes Recommendations in case of oral bitherapy failure: Diet and lifestyle recommendations Target not reached at 6 months HbA1c >7% Treatment Met + SU Met + Glitazones SU + Glitazones Oral triple therapy Met+SU + GIitazones Insulin therapy HbA1c >8%

New IDF guidelines 2011 in type 2 diabetes: Two key changes : A change in the HbA1c target to 7.0% (previously 6.5%) Algorithm TT :effectiveness, harm, cost and global availability Each step of the algorithm recommends a preferred therapy and also alternative therapies: Metformin as first line therapy(unless contraindicated) Sulfonylureas are the recommended second line Third line therapy is either a third oral agent or insulin (basal or premixed) Finally insulin should be used if the choice has been to use an oral agent as the third step, or intensification of insulin therapy if insulin had been chosen in the previous step. Stephen Colagiuri, Boden Institute, University of Sydney, Australia; MGSD CASABLANCHA 2011

Considerations for Fasting During Ramadan Religious Considerations: imposition, obligation Exemption of the sick

البقرة =183يَا أَيُّهَا الَّذِينَ آمَنُواْ كُتِبَ عَلَيْكُمُ الصِّيَامُ كَمَا كُتِبَ عَلَى الَّذِينَ مِن قَبْلِكُمْ لَعَلَّكُمْ تَتَّقُونَ =184أَيَّامًا مَّعْدُودَاتٍ فَمَن كَانَ مِنكُم مَّرِيضًا أَوْ عَلَى سَفَرٍ فَعِدَّةٌ مِّنْ أَيَّامٍ أُخَرَ وَعَلَى الَّذِينَ يُطِيقُونَهُ فِدْيَةٌ طَعَامُ مِسْكِينٍ فَمَن تَطَوَّعَ خَيْرًا فَهُوَ خَيْرٌ لَّهُ وَأَن تَصُومُواْ خَيْرٌ لَّكُمْ إِن كُنتُمْ تَعْلَمُونَ =185شَهْرُ رَمَضَانَ الَّذِيَ أُنزِلَ فِيهِ الْقُرْآنُ هُدًى لِّلنَّاسِ وَبَيِّنَاتٍ مِّنَ الْهُدَى وَالْفُرْقَانِ فَمَن شَهِدَ مِنكُمُ الشَّهْرَ فَلْيَصُمْهُ وَمَن كَانَ مَرِيضًا أَوْ عَلَى سَفَرٍ فَعِدَّةٌ مِّنْ أَيَّامٍ أُخَرَ يُرِيدُ اللَّهُ بِكُمُ الْيُسْرَ وَلاَ يُرِيدُ بِكُمُ الْعُسْرَ وَلِتُكْمِلُواْ الْعِدَّةَ وَلِتُكَبِّرُواْ اللَّهَ عَلَى مَا هَدَاكُمْ وَلَعَلَّكُمْ تَشْكُرُونَ

فتوى مجمع الفقه الإسلامي الدولي 2010 تم تصنيف المصابين بالسكري إلى اربع فئات : الفئة الأولى: المصابين بالسكري ذوو الاحتمالات الكبيرة جدا للمضاعفات الخطيرة بصورة مؤكدة : • حدوث هبوط السكر الشديد أو المتكرر أو الفقدان الحس بنقص السكر (خلال الأشهر الثلاثة التي تسبق رمضان) • حدوث الغيبوبة السكرية ) الحماض الكيتوني أو فرط التناضح) خلال الشهور الثلاثة التي تسبق رمضان • الأمراض الحادة الاخرى المرافقة للسكري • يمارسون مضطرين أعمالا بدنية شاقة • يجري لهم غسيل كلى • اثناء الحمل

فتوى مجمع الفقه الإسلامي الدولي 2010 الفئة الثانية: احتمال كبير لحدوث مضاعفات نتيجة الصيام والتي يغلب على ظن الأطباء وقوعها وتتمثل بـ: • ارتفاع السكر (180-300ملغ/دسل) و الخضاب السكري < 10% • قصور كلوي • اعتلال القلب والشرايين الكبيرة • أمراض أخرى تضيف أخطاراً إضافية عليهم • الذين يسكنون بمفردهم • كبار السن المصابون بأمراض أخرى • يتلقون علاجات تؤثر على العقل

فتوى مجمع الفقه الإسلامي الدولي 2010 حكم الفئتين الأولى والثانية: فيتعين شرعاً على المريض ان يفطر ولا يجوز له الصيام، درءاً للضرر عن نفسه، لقوله تعالى: (وَلاَ تُلْقُواْ بِأَيْدِيكُمْ إِلَى التَّهْلُكَةِ) البقرة كما يتعين على الطبيب المعالج ان يبين لهم خطورة الصيام عليهم، والاحتمالات الكبيرة لإصابتهم بمضاعفات قد تكون -في غالب الظن- خطيرة على صحتهم أو حياتهم

فتوى مجمع الفقه الإسلامي الدولي 2010 الفئة الثالثة: ذوو الاحتمالات المتوسطة للتعرض للمضاعفات نتيجة الصيام ويشمل ذلك المصابين بالسكري ذوي الحالات المستقرة والمسيطر عليها بالـ S.U. الفئة الرابعة: ذوو الاحتمالات المنخفضة للتعرض للمضاعفات نتيجة الصيام ويشمل ذلك المصابين بالسكري ذوي الحالات المستقرة والمسيطر عليها بمجرد الحمية أو بتناول العلاجات METF. حكم الفئتين الثالثة والرابعة: لا يجوز لمرضى هاتين الفئتين الإفطار، لان المعطيات الطبية لا تشير إلى احتمال مضاعفات ضارة بصحتهم وحياتهم بل ان الكثير منهم قد يستفيد من الصيام. وعلى الطبيب الالتزام بهذا الحكم وان يقدر العلاج المناسب لكل حالة على حدة.

Considerations for Fasting During Ramadan Religious Considerations: Exemption of the sick Medical Considerations: Need to define which diabetic is sick enough to be at risk and should be advised not to fast

Duration of Fast There is variation in the number of days: Depends on the moon sighting. There is variation in the number Fasting hours: Depends on the season. There is variation in the Temperature: Effect on total body fluid.

Hours of fast during the month of Ramadan Globally Day hours 24 22 20 18 16 14 12 10 8 6 4 2 Winter in the lower pale and in the summer upper pale for the year حلب رمضان 2011: إمساك 3.55 إفطار 19.44 صيام=15 ساعة درجة الحرارة 44

Change in blood glucose profile Daily glucose profile during the month of Shawal Patients were asked to test their blood sugar every two hours with a glucometer for one day during the month of Shawal as part of diet change study regardless of their diabetes management. There are three peaks for serum blood glucose following meals. The highest been following lunch and the lowest following breakfast with a mean daily glucose at 10.2 mmol/L.

Change in blood glucose with meal timing Daily glucose profile during the month of Ramadan

Change in blood glucose with meal timing Daily glucose profile for both months Risk of hypoglycemia The change in meal time will affect the glucose level through the day. There will be a prolonged period of fasting with risk of hypoglycemia. Sever hyperglycemia occur following the main meal ( ie: Eftar ). Ramadan Diabetes Study ( unpublished data )

Biochemistry of Fasting Carbohydrate metabolism In normal subjects fasting will: Decrease in serum glucose to 3.3 - 3.9 mmol ( 60-70 mg/dl ). Gluconeogenesis by liver will stop further drop of blood glucose. Insulin secretion will decrease but glucagon will increase. In diabetic subjects fasting will: Blood glucose fell within physiological limits if properly controled. Drug induced hypoglycemia is the commonest complications.

Dietary Change Calorie Change Total daily calorie intake before and during

EPI.DIA.R EPIdemiology of DIAbetes Ramadan 1422/2001     EPI.DIA.R EPIdemiology of DIAbetes Ramadan 1422/2001 Salti IS et al Diabetes Care 27: 2306-2311, 2004    

Number of patients by country (N = 12,914) Salti IS et al Diabetes Care 27: 2306-2311, 2004

Repartition by type of DM type 1 DM = 1,070 patients (8.3%) (%) type 2 DM = 11,173 patients (86.5%) DM unclassifiable = 671 patients (5.2%) Salti IS et al Diabetes Care 27: 2306-2311, 2004

Fasting during Ramadan (1) (% of patients who fast > 1 day) DM type 1 DM type 2 (%) Overall population DM type 1 = 54% DM type 2 = 86%

Results Hyperglycemia Severe Hypoglycemia 3-fold increase in T1D 5-fold in T2D (from 1 to 5 events/100pts/month) Excessive reduction in insulin doses (1/3-1/4 of patients change their insulin dose or OHAs) Increase in food intake (sugar) Severe Hypoglycemia 4-fold increase in type 1 diabetes 7-fold increase in type 2 diabetes Salti IS et al Diabetes Care 27: 2306-2311, 2004

The need for guidelines for physicians and patients The Diabetes and Ramadan Advisory Board (supported by Aventis Intercontinental) Chairmen: Ibrahim SALTI, Lebanon; Abdul JABBAR, Pakistan Members: Kamel Ajlouni, Jordan; Khalid AL-RUBEAAN, Saudi Arabia; Fahmy AMARA, Egypt; Mohamed BELHADJ, Algeria; Jamalleddine BELKHADIR, Morocco; Aissa BOUDIBA, Algeria; Said Nouou DIOP, Senegal; Ugur GORPE, Turkey; Farid HAKKOU, Morocco; Ak.Azad KHAN, Bangladesh; Adrien Lohourignon LOKROU, Ivory Coast; Jean-claude MBANYA, Cameroon; NAGATI, Tunisia; Nadim RAIS, India; Pradana SOEWONDO, Indonesia; W.Mohamed WAN BEBAKER, Malysia

RECOMMENDATIONS OF THE ADVISORY GROUP In principle, all patients with type 1 should not fast. However, if a patient insists against medical advice, please consider the following: Absolute Contra-indications: Brittle DM (as defined by the American Diabetes Association) Patients on insulin pump Patients on multiple insulin injections per day Ketoacidosis or severe hypoglycemia in the last 3 months before Ramadan People living alone Advanced micro- or macro-vascular complications Pregnancy and lactation Salti IS et al for the Diabetes and Ramadan Advisory Board. International Medical Recommendations for Muslim Subjects with Diabetes Mellitus Who Fast During the Month of Ramadan. Clinical Diabetes- Middle East, 3:143-145, 2004

Pulmonary Tuberculosis and uncontrolled infections RECOMMENDED RAMADAN GUIDELINES FOR PATIENTS WITH DIABETES MELLITUS Type 2: Continued Patients with one or more of the following are advised not to fast: Physiological conditions: Lactation Co-existing major medical conditions such as: Acute peptic ulcer Pulmonary Tuberculosis and uncontrolled infections Severe bronchial asthma People prone to urinary stones formation with frequent Urinary Tract Infections Cancer Overt cardiovascular diseases (recent MI, unstable angina) Severe psychiatric conditions Hepatic dysfunction (liver enzymes > 2 x ULN) Salti IS et al for the Diabetes and Ramadan Advisory Board. International Medical Recommendations for Muslim Subjects with Diabetes Mellitus Who Fast During the Month of Ramadan. Clinical Diabetes- Middle East, 3:143-145, 2004

RECOMMENDATIONS OF THE Advisory Group-2 Relative Contra-indications (fast with risk): Well controlled type1 DM patients No diabetes keto-acidosis (DKA) No recent hypoglycemia Not more than 2 insulin injections per day Salti IS et al for the Diabetes and Ramadan Advisory Board. International Medical Recommendations for Muslim Subjects with Diabetes Mellitus Who Fast During the Month of Ramadan. Clinical Diabetes- Middle East, 3:143-145, 2004

Nephropathy with serum creatinine more than 1.5 mg/dL RECOMMENDED RAMADAN GUIDELINES FOR PATIENTS WITH DIABETES MELLITUS Type 2: Patients with one or more of the following are advised not to fast: Conditions related to diabetes: Nephropathy with serum creatinine more than 1.5 mg/dL Severe retinopathy Autonomic neuropathy: gastroparesis, postural hypotension Hypoglycemia unawareness Major macrovascular complications: coronary and cerebrovascular Poorly controlled diabetes (Mean Random BG > 300) Multiple insulin injections per day Salti IS et al for the Diabetes and Ramadan Advisory Board. International Medical Recommendations for Muslim Subjects with Diabetes Mellitus Who Fast During the Month of Ramadan. Clinical Diabetes- Middle East, 3:143-145, 2004

I. General considerations II I. General considerations II. Pre-Ramadan medical assessment and educational counseling III. Management of patients with type 1 diabetes IV. Management of patients with type 2 diabetes: Diet-controlled patients Insulin therapy +OHAs Insulin alone V. Pregnancy and fasting during Ramadan VI. Management of hypertension and dyslipidemia Monira Al-Arouj,, Samir Assaad-Khalil,, John Buse, MDDiabetes Care August 2010 vol. 33 no. 8 1895-1902

II. Pre-Ramadan medical assessment and educational counseling

I. General considerations: Nutrition The diet during Ramadan should not differ significantly from a healthy and balanced diet It should aim at maintaining a constant body mass : 50–60% maintain their BMI 20–25% gain or lose weight (>3 kg) Avoid the ingesting of large amounts of foods rich in carbohydrate and fat Advise the ingestion of foods containing “complex” carbohydrates at the predawn meal Advise Simple carbohydrates at the sunset meal Fluid intake be increased during non fasting hours Monira Al-Arouj,, Samir Assaad-Khalil,, John Buse, MDDiabetes Care August 2010 vol. 33 no. 8 1895-1902

I. General considerations: Exercise: Normal levels of physical activity may be maintained Excessive physical activity may lead to higher risk of hypoglycemia and should be avoided particularly before the sunset meal Tarawaih prayer should be considered a part of the daily exercise program In some patients with poorly controlled type 1 diabetes, exercise may lead to extreme hyperglycemia.

I. General considerations; Breaking the fast If hypoglycemia (blood glucose of <60 mg/dl) If blood glucose reaches <70 mg/dl (3.9 mmol/l) in the first few hours after the start of the fast especially if insulin, sulfonylurea drugs, or meglitinide are taken at predawn fast if blood glucose exceeds 300 mg/dl Typical or atypical symptoms of hypoglycemia ?

III. Management of patients with type 1 DM INSULIN THERAPY It is unlikely that one injection of intermediate- or long-acting insulin administered before the evening meal would provide adequate insulin coverage for 24 h: Less flexible ( fixe dose) Hypoglycemic risk Timing during Ramadan Another option could be to use: one daily injection of the long-acting insulin analog Glargine or twice-daily injections of the insulin analog Detemir with premeal rapid-acting insulin analogs

IV. Management of patients with type 2 DM DIET-CONTROLLED PATIENTS: the risk associated with fasting is quite low there is still a potential risk for occurrence of postprandial hyperglycemia after the predawn and sunset meals combine this with a regular daily exercise program∼2 h after the sunset meal (Tarawih) older age-group, often with hypertension and dyslipidemia, fluid restriction and dehydration may increase the risk of thrombotic

IV. Management of patients with type 2 DM PATIENTS TREATED WITH ORAL AGENTS: Metformin: two thirds of the total daily dose be administered immediately before the sunset meal Glitazones no change Sulfonylureas unsuitable for use during fasting because of the inherent risk of hypoglycemia utilized with caution Use of chlorpropamide is absolutely contraindicated(gliclazide MR or glimepiride) have been shown to be effective Sulfonylureas Short-acting insulin secretagogues: repaglinide might be safer than use of

(similar to those with type 1 diabetes) IV. Management of patients with type 2 DM PATIENTS TREATED WITH INSULIN (similar to those with type 1 diabetes) Use of intermediate- or long-acting insulin preparations plus a short-acting, or premixed insulin administered before meals hypoglycemia is still a risk Using one injection of a long-acting insulin analog, such as insulin Glargine or two injections of NPH, Lente, Detemir insulin The dosage of each injection should appropriately individualized Very elderly patients may be at high risk

"Basal" Insulins: intermediate or long-acting insulins Reproduce the basal insulin secretion Inhibition of hepatic glucose production Control of FBG

LANMET: Insulin glargine or NPH insulin with metformin 9-month, comparative study of insulin glargine + metformin versus NPH + metformin in 110 patients with T2DM Insulin glargine + metformin NPH + metformin 16 12 Baseline Blood glucose (mmol/L) p=0.0047 8 p=0.07 p=0.0003 Weeks 25 - 36 4 Before breakfast After breakfast Before lunch After lunch Before dinner After dinner 22:00 04:00 Yki-Järvinen H, et al. Diabetologia 2006;49:442-51.

Events per patient-year Insulin glargine + OHAs achieves glycaemic control with low risk of hypoglycaemia Treat-to-Target is a pivotal landmark trial: Randomized comparison of OHAs + insulin glargine or NPH titrated for 24 weeks in 756 overweight insulin-naïve patients with T2DM NPH 8.56 8.61 Insulin glargine p<0.02 17.7 p<0.005 6.96 6.97 HbA1c (%) Events per patient-year 13.9 12.9 9.2 * Confirmed events of ≤4mmol/L (72 mg/dL) Riddle M, et al. Diabetes Care 2003;26:3080-6.

Percentage of patients with HbA1c <7 % without nocturnal hypoglycaemia Better response (HbA1c <7% without nocturnal hypoglycaemia) in the insulin glargine group vs. NPH % patients p<0.05 33% 27% LANTUS®

V. Pregnancy and fasting during Ramadan controversy : pregnant Muslim women are exempt from fasting some with known diabetes (type 1, type 2, or gestational) insist on fasting during Ramadan These women constitute a high-risk group, and their management requires intensive care Women with pregestational or gestational diabetes should be strongly advised to not fast during Ramadan if they insist on fasting: special attention should be given to their care Pre-Ramadan evaluation of their medical condition is essential

VI. Management of hypertension and dyslipidemia Dehydration, volume depletion A tendency toward hypotension may occur with fasting medications antihypertensive perspiration may need to be adjusted to prevent hypotension Dyslipidemia should be checked during Ramadan

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