1. An Emerging Disaster DIABETES MELLITUS

2. Session Objectives Identify the prevalence of diabetes mellitus (DM) in the Saudi community. Discuss the classification of DM. Discuss the diagnostic criteria for DM. Identify the patho-physiological changes in a diabetic patient. Enumerate and discuss the importance presenting signs & symptoms of DM.

3. Session Objectives (cont...) Investigate appropriately a patient with DM. Advice initial management plan for a patient diagnosed first with DM. Discuss different medication used in DM management. Identify importance of life style changes in diabetic patients. Discuss screening criteria for DM.

4. Genetic predisposition IGT Insulin Resistance (Hyperinsulinemia)  Cell Defect Usually 50% of  cells are functioning at time of diagnosis Type 2 Diabetes

5. Prevalence of DM in Saudi Arabia A community based study of 17232 subjects conducted between 1995 and 2000 in KSA. The examining age group, 30-70 years of selected households during 5-year period Mansour M. Al-Nozha et al,The prevalence of CAD among Saudis of both sexes, in rural as well as urban communities, as well as modifiable risk factors for CAD. Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171

6. Prevalence of DM in Saudi Arabia The overall prevalence of DM obtained from this study is 23.7% in KSA. The prevalence in males and females were 26.2% and 21.5% respectively (p<0.00001). A large number of diabetics 1116 (27.9%) were unaware of having DM. Mansour M. Al-Nozha et al,The prevalence of CAD among Saudis of both sexes, in rural as well as urban communities, as well as modifiable risk factors for CAD. Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171

7. Current DIAGNOSIS مهمه جدا – يجيك مريض ويطلب تشخيصه احفظ القيم بالمقياسين ( المللي مول والنوع الثاني )  حالات التشخيص : S ymptomatic  اولا : S ymptomatic patient plus casual plasma glucose ≥ 11.1 mmol/L or FPG ≥ 7.0 mmol/L. قراءه واحده كافيه للتشخيص اذا كان هناك اعراض  NB : FPG test done on the Plasma which only done in the Lab مهمه – الجهاز اللي بالاسواق ما يصلح لازم مختبر  OR :During an OGTT 2-hr post 75 gm-glucose ≥ 11.1 mmol/L. سيم سيم – مريض باعراض – قراءه واحده كافيه  ثانيا : In the absence of symptoms suggestive of DM, these criteria should be confirmed by repeat testing on a different day. في حاله عدم وجود اعراض يحب اعاده الاختبار للتاكيد  : ثالثا HbA1C ≥ 6.5% بدا استخدامه مؤخرا للتشخيص – مهم DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010.

8. DIAGNOSIS FPG ≤ 5.5 mmol/L = normal FPG ≥ 5.6 mmol/L to 6.9 mmol/L= IFG ( Impaired fasting glucose )  Prediabetic FPG ≥ 7.0 mmol/L = provisional diagnosis of DM and must be confirmed in asymptomatic person. (No caloric intake at least for 8 hours) HbA1C ≥ 6.5%

9. Screening FOR DM IN ASYMPTOMATIC All individuals at age 45 years or above. At younger age or more frequently in whom مهمه: ■ Are Obese ■ Have a first degree relative with diabetes ■ Are Hypertensive ≥ 140/90 ■ Have been diagnosed with GDM ■ Have Dyslipidaemia ■ Had IGT or IFG

10. Diagnosis based on: Glucose Tolerance Test 2 hr post 75 gm glucose If < 7.8 mmol/L = normal GTT If ≥ 7.8 mmol/L and < 11.1 mmol/L = Impaired GTT If ≥ 11.1 mmol/L = provisional diagnosis of Diabetes

11. Prediabetes Persons with an A1C of 5.7–6.4% المعيار الاهم للقياس حسب – القواعد العالميه الجديده, IGT, or IFG should be counseled on lifestyle changes. Three large studies of lifestyle intervention has shown sustained reduction in the rate of conversion to type 2 diabetes, 43% reduction at 20 years in the Da Qing study. 43% reduction at 7 years in the Finnish Diabetes Prevention Study (FDPS). 34% reduction at 10 years in the U.S. Diabetes Prevention Program Study (DPPS). Management : A consensus panel felt that Metformin should be the choice of drug considered. مهمه

12. Management : cont, When to add Metformin in pre-diabetes? مهمه جدا جدا In addition to lifestyle counseling, Metformin may be considered in IFG plus: نعطي الميتافورمن للحالات التاليه - مهمه  Hypertension,  Low HDL cholesterol,  Elevated triglycerides,  Family history of diabetes (first-degree relative),  Obese,  Under 60 years of age. DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010.

13. Optimal Treatment of Type 2 Diabetes means treating Hyperglycaemia and the Dysmetabolic Syndrome NEED TO TREAT Good glycaemic control Microvascular & Macrovascular Complications Insulin resistance, obesity, hyperinsulinaemia, hypertension, dyslipidaemia, atherosclerosis, procoagulant state Dysmetabolic syndrome

14. Approach to Management Diabetes management is a team work Individualize management لكل مريض حاله خاصه تختلف عن غيره Set Target goals Glycaemic Targets Bp goals Lipid goals Education Is associated with increased use of primary and preventive services and lower use of acute, inpatient hospital services.

15. ADA 1 ACE 2 HbA1c < 7.0% (general goal) ≤ 6.5% Preprandial plasma glucose 70–130 mg/dL (3.9–7.2 mmol/L) < 110 mg/dL (< 6.1 mmol/L) Postprandial plasma glucose < 180 mg/dL (< 10.0 mmol/L) < 140 mg/dL (< 7.8 mmol/L) ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; Adapted from: 1 ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care. 32:193–203; 2 American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2002; 8 (Suppl 1): 5–11; Current Treatment Goals for Glycaemic مهمه Control

16. Life Style Modification For all patients, advise for ◙ Weight Management (in overweight/obese patients can improve insulin sensitivity) ◙ Exercise (walking 150 mins / week) ◙ Diet (Provided by a Dietitian) Can reduce HbA1C by 1-2% Problems Poor adherence over time

17. ADA and EASD algorithm for the management of type 2 مخطط مهم جدا ويلخص علاج السكر النوع 2 diabetes Nathan et al., Diabetes Care 2009 SUs other than glibenclamide Insufficient clinical use to be confident regarding safety. Met=metformin; Pio=pioglitazone; SU=sulfonylurea Lifestyle and Met + intensive insulin At diagnosis: Lifestyle + Metformin Step 1Ste p 2Step 3 Lifestyle and Met + Pi o No hypoglycaemia Edema/CHF Bone loss Lifestyle and Met + DDP-4 inhibitor Lifestyle and Met + Pio + SU Lifestyle and Met + basal insulin Tier 2: Less well validated therapies الخطه تحت الدراسه وغير مثبته Lifestyle and Met + SU Lifestyle and Met + basal insulin Reinforce lifestyle interventions every visit and check HbA 1C every 3 -4 months until HbA 1C is <7% and then at least every 6 months. The interventions should be changed if HbA 1C is ≥7% Tier 1: الخطه المثبته بالدراسات Well validated therapies ننتقل من مرحله لمرحله في حاله ضعف الاستجابه – قد ياخذ ذلك سنوات SU : sulfonylurea Basal Insulin : النوع الذي يعطى لمده 24 ساعه – يوضح لاحقا

18. Life Style +Metformin Add on Oral Medication Sulphonylurea Glibenclamide Gliclazide MR Sulphonylurea Glibenclamide Gliclazide MR TZD Pioglitazone 15 -30 mg OD TZD Pioglitazone 15 -30 mg OD DPP4 inhibitor Sitagliptin (Januvia) 100 mg OD DPP4 inhibitor Sitagliptin (Januvia) 100 mg OD Hypoglycemia Weight gain Fluid retention Fractures ?Durability ?Long term risks اذا كان : A1C > 7 % Acarbose PP Hyperg 50-100 mg TDS Acarbose PP Hyperg 50-100 mg TDS Flatulence Diarrhoea مهمه جدا مهمه جدا – حفظ – اعرف كل دواء وتاثيره ومناسبته للمريض مثلا جاك مريض عنده ارتفاع سكر بعد الوجبات علاجه الامثل يكون Acarbose NB : PP hyper  post pyramidal hyperglycemia

19. : 1- Metformin تفاصيل الادويه مهم Effective & well validated therapy Choice as initial therapy Acts by reducing hepatic glucose production Other Reduces appetite & may delay absorption Improves peripheral insulin sensitivity No hypoglycemia and mild weight loss Start with 500 mg once or twice per day with meals and increase every few days till reach maximum dose of 2 gm per day.

20. Oral Medication in Type 2 DM 4- Thiozolidinediones: ● PIOGLITAZONE (15mg) Reduce insulin resistance Promotes glucose uptake by skeletal muscles and adipose tissue Inhibits hepatic gluconeogenesis Used in combination with metformin and sulphonylurea Periodic monitoring of liver enzymes Not given in patients with heart failure Recently, Debate about increase incidence of Cancer bladder ??

21. INCRETINS مجموعه ادويه جديده تعمل على هذا الانزيم - مهمه

22. Glucose in Intestine DPP-4 Plasma Mixed Meal Active Incretins Stimulate B cells (Pancreas) to secrete Insulin Inactive Incretin Renal Clearance

23. Physiological effects of GLP-1 Bunck MC, et al. Diabetologia. 2010;53 (Suppl 1):S338.

24. Glucagon-like Peptide-1 (GLP-1) مهمه شريحه  GLP-1 is secreted throughout the day by intestinal mucosa in response to oral glucose in the gut.  GLP-1 causes anabolic actions on the synthesis of insulin in beta cells by stimulating all steps of insulin biosynthesis.  GLP-1 provides continued and augmented release of insulin for secretion in response to glucose without overproduction that could lead to hypoglycemia.  GLP-1 also acts on islet alpha cells, causing strong inhibition of postprandial glucagon secretion.  GLP-1 slows gastric emptying and acts on brain to promote early satiety with reduced food intake عيب هذا العلاج الذي يعمل على هذا الانزيم انه يؤخذ على شكل ابر – مهمه

25. Dipeptidyl Peptidase-4 (DPP-4) Within minutes of secretion or exogenous administration, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 is found in many body tissues, including liver, renal, and intestinal brush- border membranes; lymphocytes; and endothelial cells.

26. INCRETINS The incretin system is impaired in patients with T2DM, which, as a consequence of its insulinotropic actions, contributes to fasting and postprandial hyperglycemia. The impairment of GLP-1 secretion varies directly with the degree of insulin resistance; those who are more insulin resistant have a lower rise in GLP-1 in response to a meal.

27. Medication:  ● Exenatide: GLP-1 receptor agonist, SC, twice-daily  ● Liraglutide: GLP-1 analog, SC, once daily ● Sitagliptin (Januvia), (DPP-4) inhibitor, 100 mg OD Other DPP-4 inhibitors, Vildagliptin, Saxagliptin, …  Type 2 diabetes only  Monotherapy or with Metformin or TZD  Weight neutral  Does not cause hypoglycemia

28. Which antidiabetic Drugs are contraindicated or should be only مهمه very cautiously when the following Co-Morbidity is present? Chronic Kidney Failure: Metformin, Acarbose, Sitagliptin, Insulin & SUs (reduced dosage) Heart Failure: TZDs Osteoporosis: TZDs Myocardial Infarction: Hypoglycemias should be avoided when Insulin or SUs are taken. Elderly people (>70 years): Hypoglycemias should be avoided when Insulin or SUs are taken.

29. Indication of Insulin in Type 2 DM مهمه If HbA1c is ≥ 9 % After maximum metformin and suphonylurea, you should consider adding Insulin and taper the Sulphonylurea.

30. Strategies for Antidiabetic Treatment Oral Triple Combination Therapy plus Basal Insulin or plus GLP-1 Oral Monotherapy Oral Dual Combination Therapy Oral Triple Combination Therapy NPH, Glargine, Levemir Metformin + Sulfonylureas + TZDs Metformin + Sulfonylureas+DPP-4- Inhib. Metformin DPP-4 Inhibitors Glinides TZDs Sulfonylureas  -Glucosidase-Inhibitors Metformin + DPP-4-Inhibitors Sulfonylureas + DPP-4-Inhibitors Metformin + Sulfonylureas Sulfonylureas + TZDs Metformin + TZDs Exenatide, Liraglutide

31. Initiation of Insulin Therapy in DM2 Complete Replacement Keep Metformin + Basal + Bolus insulin Add on Basal insulin at bed time + oral medication Types of Insulin Basal insulin (NPH, Glargine ( Lantus مهم ), Levimir) طويل التاثير يعطى مره واحده قبل النوم – يوضح بالرسومات لاحقا Premixed insulin (70/30, 75/25, 60/40, 50/50) Prandial insulin (bolus) Regular, Lispro, Aspart, NovoRapid SMBG

32. Initiation and Adjustment of Insulin≥ A1C 9% Long acting insulin (Basal) at bedtime 10 U or 0.2 U/Kg Check FG daily, increase by 2 – 4 U every 3 days until FG 70 – 130 mg/dl (3.9 – 7.2 mmol/L) if FBS > 250 mg/dl by 4-8 U. If hypoglycaemia occurs, or FG < 3.9 reduce bedtime by 4 units or 10 % which is greater If FG in range check before lunch, dinner and bedtime, add second injection. Begin with 4 -6 U of Bolus insulin before each. Adjust by 2-4 U every 3 days. Pre-bed is high add bolus insulin at dinner Pre-dinner is high add NPH at breakfast or bolus insulin at lunch Pre-lunch is high, add bolus insulin at breakfast

33. مخطط مهم Novorapid : do not cause hypoglycemia

34. 0600 0800 1800 12002400 0600 Time of day 20 4040 60 80 100 BLD Basal-Bolus Insulin Treatment With Insulin Analogues مخطط يعرض افضل خطه علاجيه – مهمه حفظ B=breakfast; L=lunch; D=dinner Glargine Lispro, or Aspart Normal pattern  U/mL

35. Glargine / Lispro Avoids fasting hyperinsulinaemia and hypoglycemia Can mimic pancreatic ß- cell insulin secretion 36% had hypoglycemia vs 50% on NPH. Glargine 50% and Lispro 50%

36. Hypoglycemia Treatment Check BG if possible. If <70 mg/dL…  Rule of 15-15-15  Give 15 grams of fast acting CHO: 3-4 glucose tablets, 1 Tb spoon honey, 3-4 sugar packets, 1 cup of milk, 5-6 hard candies,….  Wait 15 minutes and retest.  If still low take additional 15 grams of CHO  15 grams should increase Blood Glucose about 30-40 mg Glucose level treatment:  50-70 mg/dl and alert 15 grams CHO  30-50 mg/dl and alert 30 grams CHO  < 30 mg/dl and alert 45 grams CHO Glucagon should be prescribed for all individuals at significant risk of severe hypoglycemia.

37. Antiplatelet agents ● ملخص السلايد ان المريض ما يعطى اسبرين الا اذا كان عنده احد المشاكل المذكوره بالسلايد – اذا ما عنده مشاكل ما يحتاج Consider Aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk 10%). This includes most men 50 years of age or women 60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).

38. Statins and Diabetes Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients:  with CVD. (A)  without CVD who are over the age of 40 years and have one or more other CVD risk factors. (A)

39. Statins and Diabetes Low risk patients (without CVD and age of < 40) Statin therapy should be considered in addition to lifestyle therapy: if LDL cholesterol remains above 100 mg/dl or with multiple CVD risk factors.

40. Hypertension and Diabetes Goal: < 130 / 80 Choice of Medication:  ACE inhibitors  Angiotensin Receptor Blockers (ARP)

41. Influenza vaccine (yearly) Pneumococcal vaccine (once in lifetime) Vaccination

42. مهمه – سؤال Targets in DM Bp < 130 / 80 (ACEi / ARB, if not achieved add Thiazide) HbA1C ≤ 7 % (European Diab. Soc. ≤ 6.5 %) LDL-C < 100 mg/dl (2.6 mmol/L) HDL-C > 40 mg/dl (males) > 50 mg/dl (females) Trig. < 150 mg/dl (1.7 mmol/L)

45. UKPDS قراءه Aim: To determine whether intensified blood glucose control with either sulfonylurea or insulin reduces the risk of Macrovascular or Microvascular complications in type 2 diabet.

46. UKPDS Results 1997 % decreaseP Conventiona l rate Intensive rateCause 120.0294640.9 Any Diabetes related 160.05217.414.7 MI -0.5255.6 Stroke -0.151.61.1 PVD 250.002911.48.6 Microvascular L ancet 1998;352:837-853

47. UKPDS Results 2007 Sulfonylurea / Insulin Intensive Bp lowering 2007 P 2007 RRR %1997 P 1997 RRR %End Point 0.001240.009925Microvascular Disease 0.014150.05216Myocardial infarction 0.007130.446All Cause Mortality 2007 P 2007 RRR %1997 P 1997 RRR %End point 0.20160.009237Microvascular Disease 0.18110.1321Myocardial infarction 0.18110.1718All Cause Mortality

48. ◙ May 27, 2009 — A new meta-analysis suggests that intensively controlling blood glucose levels (HbA 1c ) to < 7.0%, significantly reduces the risk of (MI) and (CHD) events and has no effect on all-cause mortality and Stroke. The findings include UKPDS, ADVANCE, VADT, ACCORD, and PROACTIVE studies. ◙ The concerns stemmed particularly from the (ACCORD) and (ADVANCE) and (VADT) which showed no significant response on Macrovascular outcomes. ◙ ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.

49. PHYSICAL EXAMINATION Height and Weight (BMI) Blood Pressure (2 readings) Fundus Examination ( Hard and soft exudates, new vessel formation, macular oedema …. ) Cardiac examination Lower Limbs: ■ Skin Examination ■ Evaluation of pulses ■ Foot Examination ■ Neurologic Examination

50. مهمه LABORATORY EVALUATION FPG and 2 hr PP Midstream Urine (for Ketones, protein, pus cells,…) Urea and Creatinine Lipid Profile (total cholesterol, LDLc, HDLc and triglycerides) HbA1C ( every 3 m for insulin / every 6 m for controlled ) Test for Microalbuminuria or Albumin to creatinine ratio / 24 hr urine collection for protein / Creatinine Clearance ECG Chest X-Ray

51. Yearly Check Up: مهمه Investigations HbA1C Urea and Creatinine Lipid Profile ( Cholesterol, Triglyceride, LDL-C and HDL-C ) Albumin to creatinine ratio / 24 hour urine collection for protein Check : Eye: Fundus Examination / eye referral Feet : Visual inspection and Neurovascular status

52. TREATMENT REGIMENS OF TYPE 1 DM Conventional Insulin Therapy Two injections of NPH and Regular Insulin Mixed Insulin Two injections of 70/30 or 60/40 or 50/50 Multiple Insulin Injections ►1 or 2 injections of NPH plus 3 injections of Regular or Lispro Insulin. ►One injection of Glargine or Detemir plus 3 injections of Regular or Lispro Insulin.

53. INSULIN GLARGINE (LANTUS) The first clear long-acting insulin Acidic (pH of 4) when injected it is neutralized by the body, causing Glargine crystals to be precipitated and slowly absorbed. It is taken once a day Being acidic, cannot be mixed with other insulin

54. Initiation and adjustment of insulin regimens Long acting insulin at bedtime 10 U or 0.2 U/Kg Check FG daily, increase by 2 – 4 U every 3 days until FG 70 – 130 mg/dl (3.9 – 7.2 mmol/L) HbA1C ≥ 7% after 2-3 months If hypoglycaemia occurs, or FG < 3.9 reduce bedtime by 4 units or 10 % which is greater If FG in range check before lunch, dinner and bedtime, add second injection. Begin with 4 U before each. Adjust by 2 U every 3 days. Pre-bed is high add rapid acting insulin at dinner Pre-dinner is high add NPH at breakfast or rapid acting at lunch Pre-lunch is high, add rapid acting insulin at breakfast

55. Insulin administration Do not mix Glargine with other insulin products. Insulin site should be clean, but wiping with alcohol is not needed. Syringe reuse acceptable but meticulous attention to cleanliness is needed. Insulin pens improve the dose accuracy. Injection site rotation reduces the lipoatrophy. Abdomen region has a faster absorption rate than the Arm, which is faster than the leg.

56. American Diabetes Association Standards of Medical Care in Diabetes—2012 Referrence