DIABETES MELLITUS

1. DIABETES MELLITUS An Emerging Disaster

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

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 : • اولا :Symptomatic 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 • : ثالثاHbA1C ≥ 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/Land< 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, orIFG 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. Good glycaemic control NEED TOTREAT Dysmetabolic syndrome Insulin resistance, obesity, hyperinsulinaemia, hypertension, dyslipidaemia, atherosclerosis, procoagulant state Optimal Treatment of Type 2 Diabetes means treating Hyperglycaemia and the Dysmetabolic Syndrome Microvascular & Macrovascular Complications

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. Current Treatment Goals for Glycaemic مهمه Control ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care. 32:193–203; 2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2002; 8 (Suppl 1): 5–11;

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 Tier 1: الخطه المثبته بالدراسات Well validated therapies Lifestyle and Met + intensive insulin At diagnosis: Lifestyle+Metformin Lifestyle andMet + basal insulin ننتقل من مرحله لمرحله في حاله ضعف الاستجابه – قد ياخذ ذلك سنوات Lifestyle and Met + SU Step 1 Ste p 2 Step 3 Tier 2: Less well validated therapies الخطه تحت الدراسه وغير مثبته Lifestyle and Met + Pio Lifestyle and Met + Pio + SU No hypoglycaemia Edema/CHF Bone loss Lifestyle and Met + DDP-4 inhibitor Lifestyle andMet + basal insulin Reinforce lifestyle interventions every visit and check HbA1C every 3 -4 months until HbA1C is <7% and then at least every 6 months. The interventions should be changed if HbA1C is ≥7% SU : sulfonylurea Basal Insulin : النوع الذي يعطى لمده 24 ساعه – يوضح لاحقا SUs other than glibenclamide Insufficient clinical use to be confident regarding safety. Met=metformin; Pio=pioglitazone; SU=sulfonylurea Nathan et al., Diabetes Care 2009

18. مهمه جدا Life Style +Metformin اذا كان : A1C > 7 % Add on Oral Medication Sulphonylurea Glibenclamide Gliclazide MR DPP4 inhibitor Sitagliptin (Januvia) 100 mg OD Acarbose PP Hyperg 50-100 mg TDS TZD Pioglitazone 15 -30 mg OD Hypoglycemia Weight gain ?Durability ?Long term risks Weight gain Fluid retention Fractures Flatulence Diarrhoea 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. Mixed Meal Glucose in Intestine DPP-4 Plasma Inactive Incretin Active Incretins Stimulate B cells (Pancreas) to secrete Insulin Renal Clearance

23. Physiological effects of GLP-1Bunck 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. Metformin Sulfonylureas Glinides TZDs -Glucosidase-Inhibitors DPP-4 Inhibitors Metformin + Sulfonylureas Metformin + TZDs Sulfonylureas + TZDs Metformin + DPP-4-Inhibitors Sulfonylureas + DPP-4-Inhibitors Strategies for Antidiabetic Treatment Oral Monotherapy Oral Dual Combination Therapy Oral Triple Combination Therapy Metformin + Sulfonylureas + TZDs Metformin + Sulfonylureas+DPP-4-Inhib. Oral Triple Combination Therapy plus Basal Insulin or plus GLP-1 NPH, Glargine, Levemir 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. 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. Initiation and Adjustment of Insulin≥ A1C 9% 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 . If hypoglycaemia occurs, or FG < 3.9 reduce bedtime by 4 units or 10 % which is greater Pre-lunch is high, add bolus insulin at breakfast Pre-dinner is high add NPH at breakfast or bolus insulin at lunch Pre-bed is high add bolus insulin at dinner

33. مخطط مهم Novorapid : do not cause hypoglycemia

34. 0600 1800 0800 0600 1200 2400 Basal-Bolus Insulin Treatment With Insulin Analoguesمخطط يعرض افضل خطه علاجيه – مهمه حفظ Lispro, or Aspart U/mL 100 Glargine B L D 80 60 40 Normal pattern 20 Time of day B=breakfast; L=lunch; D=dinner

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

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 Lancet 1998;352:837-853

47. UKPDS Results 2007 Sulfonylurea / Insulin Intensive Bp lowering

48. ◙ May 27, 2009 — A new meta-analysis suggests that intensively controlling blood glucose levels (HbA1c) 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