BY Dr. HUSSEIN SAAD, MRCP (UK) Assistant Professor Consultant Family Medicine College of Medicine King Saud University DIABETES MELLITUS

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

CLASSIFICATION Type 1 diabetes (absolute insulin deficiency) Type 2 diabetes (insulin resistance with relative insulin def.) Gestational diabetes mellitus Other types (genetic or secondary types)

Prevalence of DM in Saudi Arabia A community based study of subjects conducted between 1995 and 2000 in KSA. The examining age group, 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):

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< ). 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):

Current DIAGNOSIS  S ymptomatic patient plus casual plasma glucose ≥ 11.1 mmol/L or FPG ≥ 7.0 mmol/L.  During an OGTT 2-hr post 75 gm-glucose ≥ 11.1 mmol/L.  In the absence of symptoms suggestive of DM, these criteria should be confirmed by repeat testing on a different day.  HbA1C ≥ 6.5% DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2014.

DIAGNOSIS FPG ≤ 5.5 mmol/L = normal FPG ≥ 5.6 mmol/L to 6.9 mmol/L= IFG FPG ≥ 7.0 mmol/L = provisional diagnosis of DM and must be confirmed in asymptomatic person. HbA1C ≥ 6.5% If two different tests (such as A1C and FPG) are both above the diagnostic thresholds the diagnosis of diabetes is confirmed.

Screening FOR DM IN ASYMPTOMATIC All individuals at age 45 years or above. At younger age or more frequently in whom: ■ Are Obese ■ Have a first degree relative with diabetes ■ Are Hypertensive ≥ 140/90 ■ Have been diagnosed with GDM ■ Have Dyslipidaemia ■ Had IGT or IFG or HbA1C ≥ 5.7 ■ Women with polycystic ovarian syndrome (POS) Women with polycystic ovarian syndrome (PCOS) ≥

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

Prediabetes Persons with an A1C of 5.7–6.4%, 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). A consensus panel felt that Metformin should be the choice of drug considered.

When to add Metformin in pre-diabetes? In addition to lifestyle counseling, Metformin is considered in IFG plus:  Hypertension,  Low HDL cholesterol,  Elevated triglycerides,  Family history of diabetes (first-degree relative),  Obese,  Under 60 years of age. DIABETES CARE, JANUARY 2012.

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

Approach to Management Diabetes management is a team work Individualize management 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.

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 Control

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

ADA algorithm for the management of type 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 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: Well validated therapies

Life Style +Metformin Add on Oral Medication Sulphonylurea Glibenclamide Gliclazide MR Sulphonylurea Glibenclamide Gliclazide MR TZD Pioglitazone mg OD TZD Pioglitazone 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 A1C > 7 % Acarbose PP Hyperg mg TDS Acarbose PP Hyperg mg TDS Flatulence Diarrhoea

Metformin 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.

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 ??

INCRETINS

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

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

Glucagon-like Peptide-1 (GLP-1)  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

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.

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.

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

Which antidiabetic Drugs are contraindicated or should be only 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.

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

Antiplatelet agents ● 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).

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)

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.

Hypertension and Diabetes Goal: < 140 / 80 Choice of Medication:  ACE inhibitors  Angiotensin Receptor Blockers (ARP)

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

Targets in DM Bp < 140 / 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)

UKPDS 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.

UKPDS Results 1997 % decreaseP Conventiona l rate Intensive rateCause Any Diabetes related MI Stroke PVD Microvascular L ancet 1998;352:

UKPDS Results 2007 Sulfonylurea / Insulin Intensive Bp lowering 2007 P 2007 RRR %1997 P 1997 RRR %End Point Microvascular Disease Myocardial infarction All Cause Mortality 2007 P 2007 RRR %1997 P 1997 RRR %End point Microvascular Disease Myocardial infarction All Cause Mortality

◙ 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.

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

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

Yearly Check Up: 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

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.

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

Time of day BLD Basal-Bolus Insulin Treatment With Insulin Analogues B=breakfast; L=lunch; D=dinner Glargine Lispro, or Aspart Normal pattern  U/mL

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

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

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.

CASE 1 A 53-year-old man presents to your office to check the results of some routine investigations. BP 134 / 76 BMI 29.4 FPG : 6.6 mmol/L In another occasion FPG: 6.2 HbA1C: 6.1 % What is your management plan?

CASE 2 A 48-year-old man presents to your office for routine checkup for hypertension. Asymptomatic. On Bisoprolol 5 mg a day. FH : his father is diabetic BMI 36 Bp: 148/92 FPG: 10.3 mmol/L U and E: normal Cholesterol: 5.8 mmol/L LDL: 3.78 HDL: 0.88 Trig mmol/L What are the next actions?  Diagnosis  Choice of medication for HTN, Lipids  Further work up

Case 3 Mohammed a 35 year old referred from A/E because of being recently diagnosed diabetic. He was put on glibenclamide 5 mg per day. A/E: RBS: 38.3 Urine: Ketones 3+ Glucose 4+ BMI 36 Bp 120 / 72 In clinic RBS by glucocheck: 14.7 Chol. 5.8 LDL-C: 4.3 HDL-C: 0.8 Trig. 2.1 Hb A1C: 11.1 % 24 hr urine for protein: gm (0.01 – 0.15) Creatinine Clearance: ml/min (75 – 125) How are you going to manage him?

CASE 4 A 44-year-old woman presents to your office with 2 month H/O loss of weight and polyuria. BMI 20 RBS : 24.4 mmol/L Urine dipstick : glucose: 4+ ketones : nil Protein : ++ What is your plan of management ?

Case 5 A 22-year-old university student, presents to your office with one week H/O fatigue and nocturia. He lost 6 kg per last month. RBS : 24.6 mmol/L What is the most important next step to do ?

CASE 6 A 52-year-old man is known case of DM presents to your office for follow up. BMI 33 He is on : Glibenclamide 10 mg po bid Metformin 1 gm po Bid FBS : 16.2 mmol/L Cholesterol : 7.3 mmo/L HbA1C: 11.6 % LDL-C : 4.8 mmol/L HDL-C : 0.88 mmol/L Trig. 4.6 mmol/L U& E : norm. How are you going to manage this patient ?

American Diabetes Association January 2014 Referrence