RISK FACTORS FOR DM2: Age 40 First-degree relative with DM2 High-risk population (Aboriginal, African, Asian Hispanic, South Asian) Overweight

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1 TYPE 2 DIABETES: 90% of diabetes cases Progressive loss of beta cell function with insulin resistance May range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance Multifactorial pathophysiology involving multiple organ systems RISK FACTORS FOR DM2: Age 40 First-degree relative with DM2 High-risk population (Aboriginal, African, Asian Hispanic, South Asian) Overweight SCREENING CHECKLIST: SCREEN every 3 years if 40 or high risk on risk calculator USE fasting plasma glucose (FPG) 7.0 mmol/l and/or A1C 6.5% as initial screening tests DIAGNOSIS OF PREDIABETES & DIABETES: Test Advantages Disadvantages FPG No caloric intake for at least 8h Established standard Sample not stable (mmol/l) = IFG Fast & easy Day-to-day variability 7.0 = diabetes Single sample Inconvenient to fast Glucose homeostasis in single time point 2hPG in a = IGT Established standard Sample not stable 75 g OGTT 11.1 = diabetes Day-to-day variability (mmol/l) Inconvenient, unpalatable, cost Random PG 11.1 = diabetes (mmol/l) A1C (%) Gold standard for following long-term control, Convenient Expensive diagnosis, med adjustment Single sample Affected by medical conditions, aging, o Surrogate marker for risk of complications Low day-to-day variability ethnicity Measures % of HbA irreversibly bound to glucose Reflects long term [glucose] Standardized, validated assay required Indicator of glucose control over last 3 months No fasting Not used for age <18, pregnant women, o Mean BG in 30 days immediately preceding No daily testing (q3-6 m) suspected DM1 or hemoglobinopathies sample = 50% of results Usually done at lab (or Average blood glucose levels over the last 3 o Prior days = 10% pharmacy) months (i.e. does not measure day-to-day BG) o A1C may be at target but actual blood = prediabetes glucose levels may be very high and very 6.5 = diabetes low (but average out to normal) o Pt sx should give clue if this is happening A1C x = average BG No immediate feedback (diet, exercise, medications, stress all impact BG) If rate of RBC turnover is altered, A1C may not accurately reflect glycemic status TARGET A1C For most patients: A1C 7.0% o Preprandial sugar: h postprandial sugar: A1C 6.5% may be considered to further lower risk of nephro and retino -pathy (balanced against risk of hypoglycemia) Consider % if: Limited life expectancy High level of functional dependency Extensive CAD at high risk of ischemic events Multiple co-morbidities History of recurrent severe hypoglycemia Hypoglycemia unawareness Longstanding diabetes difficult to achieve A1C 7%, despite optimal antihyperglycemic therapy (including combo and intensified basal-bolus insulin therapy) SELF-MONITORING BLOOD GLUCOSE: Regular SMBG SMBG 4 times per day when using multiple daily injections ( 4 times per day) or on insulin pumps SMBG at least as often as insulin is being given (using insulin < 4 times per day) SMBG individualized and may involve SMBG 4 times per day Pregnant (or planning a pregnancy), whether using insulin or not Hospitalized or acutely ill SMBG individualized and may involve SMBG 2 times per day Starting a new medication known to cause hyperglycemia (ex// steroids) Experiencing an illness known to cause hyperglycemia (ex// infection) Increased frequency of SMBG SMBG at times when sx of hypoglycemia occur or at times when hypoglycemia has previously occurred (esp. using hypoglycemic agents) SMBG as often as required by employer for occupation that requires strict avoidance of hypoglycemia SMBG 2 times per day to assist in lifestyle and/or medication changes until glycemic targets are met SMBG 1 time per day (at different times of day) to learn the effects of various meals, exercise and/or medications on blood glucose when newly diagnosed with diabetes (< 6 months) Some people with diabetes (treated with lifestyle and/or oral agents AND meeting glycemic targets) still may benefit from very infrequent checking (SMBG once or twice per week) to ensure glycemic targets are being met between A1C tests Daily SMBG Treated with only lifestyle AND is meeting glycemic targets not required Has pre-diabetes

2 LIFESTYLE CHANGES: DIET: PLATE METHOD HAND METHOD: Fruits/grains/starches: each size of fist Veggies: hold in both hands Milk: 250 ml low-fat milk with meal Meat: size of palm and thickness of little finger Fats: tip of thumb CANADA FOOD GUIDE TIPS: Control of blood glucose may be helped by: o Consistency in carb intake o Spacing & regularity of meal consumption (3 meals daily no more than 6h apart) Replace high GI carbs with low GI carbs in mixed meals o Clinically significant benefit for glycemic control in people with DM1 and DM2 o GI (glycemic index) = measures how quickly a food raises the blood glucose Including snacks should be individualized based on meal spacing, metabolic control, treatment regimens, risk of hypoglycemia, risk of weight gain Emphasize choices low in energy density, high in volume o Limit sugars, sweets, and sugary drinks o Limit high fat foods o Eat more high fibre foods o If thirsty drink water MODEST WEIGHT LOSS MAKES A DIFFERENCE: Goal is to prevent weight gain, promote weight loss and prevent weight re-gain Weight loss of only 5-10% improves: o Insulin sensitivity o Glycemic control o Blood pressure o Lipid levels CDA PHYSICAL ACTIVITY RECOMMENDATIONS: For most people, being sedentary has far greater adverse health consequences than exercise would Before beginning a program of physical activity more vigorous than brisk walking, diabetics should be assessed for conditions (ex// heart disease) that might place them at increased risk for an adverse event associated with certain types of exercise AEROBIC EXERCISE RESISTANCE EXERCISE At least 150 mins of aerobic exercise per week at mod to vigorous intensity At least 2 (preferably 3) sessions per week of resistance exercise o Moderate intensity: 50-70% of a person s max heart rate (can talk but (including elderly people) not sing your favourite song) o Initial instruction & periodic supervision by an exercise o Vigorous intensity: > 70% of a person s max heart rate (won t be able specialist is recommended to say more than a few words w/o pausing for a breath) Improves glycemic control, decreases insulin resistance and Should be spread over at least 3 days and no more than 2 days w/o exercise increases muscle strength Lasts at least for 10 mins at a time Is physical activity involving brief repetitive exercises with weights, o Pts with very low fitness may need to begin with as little as 5 mins per day and increase volume & intensity gradually over time weight machines, resistance bands or one s own body weight (ex// push ups) to increase muscle strength and/or endurance Is physical activity such as walking, bicycling, or jogging that involves o Start with 1 set of reps at moderate weight continuous, rhythmic movements of large muscle groups o Progress to 2 sets of reps o Progress to 3 sets of 8 reps at heavier weight

3 Drugs Benefits Counselling points (AEs and considerations) Sulfonylureas Reduce micro- and macro- Hypoglycemia (chlorpropamide, glyburide > others) = take with food bid (but not at HS) Chlorpropamide vascular complications Consider 1.25 mg po daily (question new dose of glyburide 5-10 mg po bid!!) Gliclazide Reduce death Sick day list (SAD MAN) Glimepiride A1C reduction: Weight gain Glyburide GI: nausea, fullness, bloating (minimize by taking with food; suggested 30 mins pre-meals) Tolbutamide Sulfa allergy (although structure differs from sulfonamides) Metformin Reduce micro- and macro- GI: diarrhea, abd. discomfort, metallic taste, nausea, anorexia vascular complications o Dose-related & subsides with time = start low & increase slowly Reduce death mg cc main mealincrease by mg weekly1 g bid (usual dose) Weight LOSS Lactic acidosis (rare): weakness, malaise, heavy labored breathing, drowsiness, abd. distress Rare hypoglycemia Do not use metformin in: Improves insulin resistance o Renal impairment (egfr < 60 caution, <30 contraindicated); elderly until renal fxn known A1C reduction: o Hepatic disease, history of lactic acidosis, excessive alcohol (acute or chronic) o Septicemia, dehydration, hypoxemia Hold before and 48 h after pyelography or angiography (can cause AKI) Alpha-glucoside No long-term studies Flatulence, diarrhea, abd. pain (improve over time) inhibitors Lowers post-prandial BG o Start low (25 mg daily) increase slowly (by 25 mg per meal increments over 6-8 wks) Acarbose A1C reduction: Hypoglycemia when combined with sulfonylureas or meglitinides Meglitinides No long-term studies Hypoglycemia Repaglinide A1C reduction: Weight gain Nateglinide o Repag > nateg Useful in people with sulfa allergies or intolerant to sulfonylureas Thiazolidinedione Not used as first line Rosiglitazone may increase risk of MI (must undergo CV safety studies & sign informed consent) Rosiglitazone A1C reduction: Increase plasma volume (can worsen edema) = contraindicated in CHF Pioglitazone o Watch for unusual weight gain, SOB, edema, weakness, fatigue Troglitazone (6-12 wks before max effect) Weight gain (withdrawn due Hepatotoxicity = contraindicated if hepatic dysfunction to acute liver o Measure LFTs at baseline, q2m x 1 yr, then periodically failure) o D/C if ALT > 3x normal, bilirubin, or sx (fatigue, NV, abd. pain, dark urine) Not approved for use with insulin DPP-4 inhibitors Weight neutral Sitagliptin: 100 mg po daily 50 mg po daily when egfr mg po daily when egfr < 30 Sitagliptin Rare hypoglycemia Nasopharyngitis, headache, nausea, diarrhea, arthralgias, pancreatitis (??), allergic reactions Saxagliptin Saxa and lina covered by Saxagliptin: 5 mg po daily when egfr > mg po daily when egfr 50 Linagliptin PharmaCare Nasopharyngitis, bronchitis, hypersensitivity (rash, urticaria), pancreatitis (?), increased risk of HF Alogliptin A1C reduction: More interactions than other DPP4-inhibitors ( with diltiazem, ketoconazole; with rifampin) Linagliptin: 5 mg po daily (don t use in severe renal impairment) Headache, arthralgia, back pain, nasopharyngitis, hyperuricemia, pancreatitis (?) Alogliptin: 25 mg po daily 12.5 mg po daily when egfr mg po daily when egfr < 30 Vomiting, peripheral edema, anemia, neutropenia, nasopharyngitis GLP-1 receptor Weight loss Liraglutide: start with 0.6 mg daily x 1 wk (to reduce GI sx) increase to 1.2 mg SC daily (up to 1.8 mg) agonists (injectables) Rare hypoglycemia CrCl < 50: Clinical Pharm 2000 says no dosage adjustment, but monograph says contraindicated Liraglutide A1C reduction: Contraindicated if personal or family hx of medullary thyroid carcinoma or multiple endocrine Dulaglutide neoplasia syndrome type 2 Exenatide o Animal studies: dose and treatment-duration dependent thyroid c-cell tumors o Monitor: mass in neck, dysphagia, dyspnea, persistent hoarseness o Unknown if serum calcitonin monitoring or thyroid ultrasound useful (low specificity) NVD, jittery, dizziness, headache, dyspepsia Store in fridge but when using can keep at room temp x 1 month Dulaglutide: start at 0.75 mg weekly may increase to 1.5 mg weekly Similar SEs, warnings, precautions as liraglutide Exenatide: 5 mcg SC bid (w/in 60 mins of meals, at least 6h apart) x 1 m can increase to 10 mcg bid May need to reduce dose of sulfonylurea by 50% Do not use if CrCl < 30 or severe GI disease (gastroparesis) Nausea (dose-dependent, resolves), pancreatitis, anti-exenatide Ab titers (significance unknown) Slows gastric emptying (take meds 1h before injecting and with snacks) SGLT2 inhibitors Low risk of hypoglycemia Diuretic increased risk of dehydration Canagliflozin Empa shows decreased Increased risk of UTI and genital yeast infections Dapaglifozin mortality, death from CV Lower BP, weight loss, increased LDL Empaglifozin causes, hospitalizations o Take in morning (except dapagliflozin can be taken at any time of the day) from HF o Drink lots of water (esp. during first 3 days), esp. if on ACEI/ARB or have lower BP A1C reduction: Monitor potassium (esp. if on ACEI/ARB or K-sparing diuretic) Diabetic ketoacidosis? Fractures? Bladder cancer risk if combining dapag with pioglitazone?? Can decrease egfr (but this recovers) Don t start canag if egfr < 60, contraindicated if <45; dapag CI if < 60; empag CI if < 45 o Doesn t get to site of action and ADRs increased Insulin Reduced micro and macro Hypoglycemia (must carry sugar at all times) vascular complications Weight gain Reduced death COMBO THERAPY: insulin + oral agent slow intro to insulin, smaller insulin dose, less A1C reduction: varies hypoglycemia, reduce weight gain associated with insulin

4 PROGRESSION OF DIABETES: 60% of T2DM will eventually require insulin therapy to adequately control BG levels Only 40% meet A1C target of 7% o Only 6% of those not at target were being considered for insulin therapy o Increase in insulin dose only considered for 10% pts not at A1C target USING INSULIN IN T2DM: When glycemic control is inadequate At diagnosis when A1C 8.5% Metabolic decompensation End organ failure Pregnancy & planning pregnancy Temporarily during acute illness, stress, medical procedure/surgery PSYCHOLOGICAL INSULIN RESISTANCE: Means personal failure Fear of needles Lack of belief in efficacy of insulin Fear of complications and hypoglycemia Inconvenient, time consuming, restrictive Weight gain Physician resistance INITIATING INSULIN IN TYPE 2: GENERAL STRATEGIES: Tailor to individual (many options) o Start with bedtime insulin in addition to oral antihyperglycemic agents o Basal plus Strategy o Starting with Premixed insulin o Starting with Intensive insulin therapy Patients can be taught self-titration o Do not titrate further if 2 episodes of hypoglycemia in the week or any nocturnal hypoglycemia Oral antihyperglycemic agents o Metformin continued o Other agents: reduction or D/C (depends on hypoglycemic episodes) o TZDs stopped (CI for use with insulin because they increase HF) DISCUSS WITH PATIENT: Initiation regimen Type and starting dose of insulin, explain onset, peak, duration, prep, storage Titration schedule, when to check and what blood glucose targets are being used Explain amount of insulin that may be needed (0.5 1 U/kg but higher in very insulin resistant patients) Hypoglycemia: sx, prevention, txt Sick day guidelines Driving guidelines Injection device, technique, rotation of site Follow up to discuss concerns PATTERN MANAGEMENT: Review of all parameters that affect BG Involves reviewing a record of glucose values, food, physical activity, medication administration and other factors DO NOT REACT TO ONE BG VALUE o 3-4 days of info required to determine a pattern Organize results so BG values from same time of day are seen and reviewed together STRATEGY #1: BASAL ADDED TO ORAL ANTIHYPERGLYCEMICS Insulin: NPH, Glargine, Detemir Starting dose: 10 U daily at bedtime o Titration: 1 unit per day until FBG 4-7 achieved o FBG consistently < 5.5, consider reducing 1-2 U to avoid nocturnal hypoglycemia Monitor: at least 1/day FBG Oral antihyperglycemics may need to be reduced if daytime hypoglycemia occurs STRATEGY #2: BASAL PLUS STRATEGY Optimize basal dose to fasting target Starting dose: 2-4 units o Titration: measure BG prior to meal then titrate 1 unit daily to either target: 2 hr post meal of 10 mmol/l ( 8 mmol/l in certain cases) Pre-meal BG of next meal to 4-7 mmol/l o Keep carb intake constant while titrating If intensification needed, add a meal tine (bolus) insulin to either main meal or breakfast Oral antihyperglycemics may need to be reduced/stopped if daytime hypoglycemia occurs STRATEGY #3: STARTING WITH PRE-MIXED INSULIN Insulin: Human 30/70, NovoMix 30, Humalog Mix 25/50 o Human premixes injected min before meal o Analogue biphasic insulin injected right before meal Starting dose: 5-10 U pre-breakfast and/or pre-supper o Titration: 1-2 U until BG target of 4-7 Pre-breakfast premix is titrated to pre-supper target premix is titrated to pre-breakfast (fasting) target o Self-monitor twice daily to safely titrate o Stop increasing when both targets are meat Oral antihyperglycemics may need to be reduced/stopped at start of regimen or when daytime hypoglycemia occurs STRATEGY #4: INTENSIVE INSULIN THERAPY WITH BASAL/BOLUS INSULIN Calculate total daily dose of units/kg, then distribute: o 40% of total daily dose as basal insulin o 20% of total daily dose as bolus insulin 3 times per day Titration for analogue insulin: o Pre-breakfast BG adjust long-acting basal o Pre-lunch BG adjust am rapid bolus o BG adjust lunch rapid bolus o Pre-bedtime BG adjust supper rapid bolus Measure blood glucose 4 times daily before meals and bedtime Stop all anti-hyperglycemics except metformin PRIORITIZING TREATMENT: if a pattern appears: 1. Always fix hypoglycemia (< 4.0 mmol/l) first 2. Bring fasting BG into target 3. Work on hyperglycemia patterns, usually looking at pre-meal values followed by postmeal values ADJUSTING INSULINS: Adjust only one insulin at a time (the one that affects the BG you are concerned with) Adjust insulin dose by no more than 10% at a time Reassess BG values after several days before making further changes BASAL/BOLUS: BID COMBO OF PRE-MIXED INSULIN: BG value at: Adjust: BG value at: Adjust: Fasting/pre-breakfast Bedtime basal Fasting/pre-breakfast Pre-lunch Breakfast bolus Pre-lunch Pre-breakfast Lunch bolus Pre-breakfast Bedtime Supper bolus Bedtime

5 INSULIN EDUCATION SESSION: STORAGE: Unopened: refrigerate (not on fridge door) Opened: room temp x 28 days o Detemir, Glargine U 300 < 30 o C x 42 days Inspect appearance o Clear insulin should be clear o Cloudy insulin should not be clumped DO NOT SHAKE o Re-suspend properly SICK DAY GUIDELINE ADVISE: Blood sugar rises with illness o Check more often Drink plenty of extra sugar-free fluids/water If can t eat, replace wi/ sugar-containing liquids o Try to consume 15 g carbs every hr Vomiting, diarrhea > 2x/4h see doctor Discuss with healthcare team plan to adjust insulin during illness INJECTING INSULIN: New syringe/needle tip with each injection o Avoids lipohypertrophy (which can reduce insulin absorption by up to 37%) Regardless of BMI: needle length 6 mm syringe or 4 mm pen is appropriate o SC tissue right below skin layer, and thickness of skin is SAME across BMI o Injecting into skin/muscle can cause insulin to be absorbed faster SC injection o Count to 10 before removing needle Abdomen: fastest, most consistent absorption (then upper arms, thigh, buttocks) o Rotate injections within a zone x 1 wk Clean & dry, alcohol unnecessary Each injection 1-2 cm from each other w/in the zone being used o Rotate injection zone weekly, site daily Abdomen: 4 zones Thighs: 2 zones on each leg Buttocks: 2 zones (one each) Arms: 2 zones (one on each) If using syringe, a skin lift is necessary (hold till injection complete) o Skin lift not necessary with 4 mm pen Dispose of sharps in approved sharps container HYPOGLYCEMIA: Lower rates with rapid acting analogues than regular insulin Less nocturnal hypoglycemia with long-acting basal insulin analogues than NPH Causes: missed, smaller, or delayed meals; unplanned or extra activity; consuming alcohol HYPOGLYCEMIA CHECKLIST: Recognize hypoglycemia and confirm Differentiate mild-mod vs. severe Treat hypoglycemia but avoid overtreatment Avoid hypoglycemia in the future SYMPTOMS OF HYPOGLYCEMIA: Early signs Late signs Trembling, shaking Difficulty concentrating Dizzy, light headed Confusion Palpitations, sweating, anxiety Changed behavior Hunger Drunk-like behavior Nausea, headache Trouble speaking Tingling, blurred vision Loss of consciousness Symptoms vary from person to person HYPOGLYCEMIA TREATMENT: Check BG < 4.0 mmol/l < 2.9 & conscious <2.9 & unconscious 15 gm fast acting carbs 20 gm fast acting carbs Inject 1 mg glucagon 3-4 dextrose tabs 7 dextrose tabs SC or IM and call 15 ml (3 packets) table sugar or honey 250 ml juice or regular soda emergency services 175 ml juice or regular 4 tsp sugar soft drink 8 lifesavers 6 lifesavers Wait 15 mins, retest BG and retreat with another 15 gm carb if BG still < 4.0 mmol/l If next meal is >1 h away once hypoglycemia has been reversed, have a snack with 15 gm carbs and a protein source HYPOGLYCEMIA AND DRIVING: SAFE BG PRIOR TO DRIVING = BG 5.0 mmol/l If BG < 5 prior to driving: take 15 g carbs, re-check in 15 mins If BG < 4, wait at least 45 mins after BG 5 If BG , safe to drive once BG 5 NEED TO RE-CHECK BG EVERY 4 H OF CONTINOUS DRIVING (and carry simple carb snacks) INSULIN PENS: Consult directions with each pen New needle tip for each injection Never leave needle on pen Re-suspend cloudy insulin, tap to send any air bubbles to needle end Prime with a 2 unit shot each time drop of insulin should appear o Repeat until a drop appears Dial dose and inject at 90 degrees o 4 mm needle inserted at 90 o safely & consistently deposits insulin in SC space >99.5% of time Count slowly to 10 then remove from skin PATIENTS SHOULD LEAVE FROM INSULIN STARTING SESSION WITH: Insulin, pen or syringes, sharps container Dose of insulin, when to inject and titration protocol Knowing injection technique: how, where, site rotation Hypoglycemia sheet for S/S and treatment Driving guidelines Log book, test times, blood glucose targets Appointment for follow-up call