lecture 40 and 41 therapeutics of dm2 cooke/dossa … · screen every 3 years if ≥ 40 or high...

Lecture 40 and 41 Therapeutics of DM2 Cooke/Dossa

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 (mmol/L)

No caloric intake for at least 8h

6.1 – 6.9 = IFG

≥ 7.0 = diabetes

Established standard

Fast & easy

Single sample

Sample not stable

Day-to-day variability

Inconvenient to fast

Glucose homeostasis in single time point

2hPG in a 75 g OGTT (mmol/L)

7.8 – 11.0 = IGT

≥ 11.1 = diabetes

Established standard Sample not stable

Day-to-day variability

Inconvenient, unpalatable, cost

Random PG (mmol/L)

≥ 11.1 = diabetes

A1C (%) Gold standard for following long-term control, diagnosis, med adjustment o Surrogate marker for risk of complications

Measures % of HbA irreversibly bound to glucose

Indicator of glucose control over last 3 months o Mean BG in 30 days immediately preceding

sample = 50% of results o Prior 90-120 days = 10%

6.0 – 6.4 = prediabetes

≥ 6.5 = diabetes

A1C x 1.59 – 2.59 = average BG

Convenient

Single sample

Low day-to-day variability

Reflects long term [glucose]

No fasting

No daily testing (q3-6 m)

Usually done at lab (or pharmacy)

Expensive

Affected by medical conditions, aging, ethnicity

Standardized, validated assay required

Not used for age <18, pregnant women, suspected DM1 or hemoglobinopathies

Average blood glucose levels over the last 3 months (i.e. does not measure day-to-day BG) o A1C may be at target but actual blood

glucose levels may be very high and very low (but average out to normal)

o Pt sx should give clue if this is happening

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: 4.0 – 7.9

2h postprandial sugar: 5.0 – 10.0

A1C ≤ 6.5% may be considered to further lower risk of nephro and retino -pathy (balanced against risk of hypoglycemia)

Consider 7.1 -8.5% 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 anti-hyperglycemic 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 not required

Treated with only lifestyle AND is meeting glycemic targets

Has pre-diabetes


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 o Moderate intensity: 50-70% of a person’s max heart rate (can talk but

not sing your favourite song) o Vigorous intensity: > 70% of a person’s max heart rate (won’t be able

to say more than a few words w/o pausing for a breath)

Should be spread over at least 3 days and no more than 2 days w/o exercise

Lasts at least for 10 mins at a time 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

Is physical activity such as walking, bicycling, or jogging that involves continuous, rhythmic movements of large muscle groups

At least 2 (preferably 3) sessions per week of resistance exercise (including elderly people) o Initial instruction & periodic supervision by an exercise

specialist is recommended

Improves glycemic control, decreases insulin resistance and increases muscle strength

Is physical activity involving brief repetitive exercises with weights, weight machines, resistance bands or one’s own body weight (ex// push ups) to increase muscle strength and/or endurance o Start with 1 set of 10-15 reps at moderate weight o Progress to 2 sets of 10-15 reps o Progress to 3 sets of 8 reps at heavier weight


Drugs Benefits Counselling points (AEs and considerations)

Sulfonylureas

Chlorpropamide

Gliclazide

Glimepiride

Glyburide

Tolbutamide

Reduce micro- and macro- vascular complications

Reduce death

A1C reduction: 1 – 1.5

Hypoglycemia (chlorpropamide, glyburide > others) = take with food bid (but not at HS)

Consider 1.25 mg po daily (question new dose of glyburide 5-10 mg po bid!!)

Sick day list (SAD MAN)

Weight gain

GI: nausea, fullness, bloating (minimize by taking with food; suggested 30 mins pre-meals)

Sulfa allergy (although structure differs from sulfonamides)

Metformin Reduce micro- and macro- vascular complications

Reduce death

Weight LOSS

Rare hypoglycemia

Improves insulin resistance


GI: diarrhea, abd. discomfort, metallic taste, nausea, anorexia o Dose-related & subsides with time = start low & increase slowly

250-500 mg cc main mealincrease by 250-500 mg weekly1 g bid (usual dose)

Lactic acidosis (rare): weakness, malaise, heavy labored breathing, drowsiness, abd. distress

Do not use metformin in: o Renal impairment (eGFR < 60 caution, <30 contraindicated); elderly until renal fxn known 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 inhibitors

Acarbose

No long-term studies

Lowers post-prandial BG

A1C reduction: 0.5 – 0.8

Flatulence, diarrhea, abd. pain (improve over time) o Start low (25 mg daily) increase slowly (by 25 mg per meal increments over 6-8 wks)

Hypoglycemia when combined with sulfonylureas or meglitinides

Meglitinides

Repaglinide

Nateglinide

No long-term studies

A1C reduction: 1 – 1.5 o Repag > nateg

Hypoglycemia

Weight gain

Useful in people with sulfa allergies or intolerant to sulfonylureas

Thiazolidinedione

Rosiglitazone

Pioglitazone

Troglitazone (withdrawn due to acute liver failure)

Not used as first line


(6-12 wks before max effect)

Rosiglitazone may increase risk of MI (must undergo CV safety studies & sign informed consent)

Increase plasma volume (can worsen edema) = contraindicated in CHF o Watch for unusual weight gain, SOB, edema, weakness, fatigue

Weight gain

Hepatotoxicity = contraindicated if hepatic dysfunction o Measure LFTs at baseline, q2m x 1 yr, then periodically 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

Sitagliptin

Saxagliptin

Linagliptin

Alogliptin

Weight neutral

Rare hypoglycemia

Saxa and lina covered by PharmaCare


Sitagliptin: 100 mg po daily 50 mg po daily when eGFR 30 – 50 25 mg po daily when eGFR < 30

Nasopharyngitis, headache, nausea, diarrhea, arthralgias, pancreatitis (??), allergic reactions

Saxagliptin: 5 mg po daily when eGFR > 50 2.5 mg po daily when eGFR ≤ 50

Nasopharyngitis, bronchitis, hypersensitivity (rash, urticaria), pancreatitis (?), increased risk of HF

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 30-60 6.25 mg po daily when eGFR < 30

Vomiting, peripheral edema, anemia, neutropenia, nasopharyngitis

GLP-1 receptor agonists (injectables)

Liraglutide

Dulaglutide

Exenatide

Weight loss

Rare hypoglycemia


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)

CrCl < 50: Clinical Pharm 2000 says no dosage adjustment, but monograph says contraindicated

Contraindicated if personal or family hx of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2

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

Canagliflozin

Dapaglifozin

Empaglifozin

Low risk of hypoglycemia

Empa shows decreased mortality, death from CV causes, hospitalizations from HF

A1C reduction: 0.7 – 1

Diuretic increased risk of dehydration

Increased risk of UTI and genital yeast infections

Lower BP, weight loss, increased LDL o Take in morning (except dapagliflozin can be taken at any time of the day) o Drink lots of water (esp. during first 3 days), esp. if on ACEI/ARB or have lower BP

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 vascular complications

Reduced death

A1C reduction: varies

Hypoglycemia (must carry sugar at all times)

Weight gain

COMBO THERAPY: insulin + oral agent slow intro to insulin, smaller insulin dose, less hypoglycemia, reduce weight gain associated with insulin


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

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

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

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)

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 30-45 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 Pre-supper 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 0.3 – 0.5 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 Pre-supper 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

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

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 post-meal 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:

BG value at: Adjust:

Fasting/pre-breakfast Bedtime basal

Pre-lunch Breakfast bolus

Pre-supper Lunch bolus

Bedtime Supper bolus

BID COMBO OF PRE-MIXED INSULIN:

BG value at: Adjust:

Fasting/pre-breakfast Pre-supper

Pre-lunch Pre-breakfast

Pre-supper Pre-breakfast

Bedtime Pre-supper


INSULIN EDUCATION SESSION:

STORAGE:

Unopened: refrigerate (not on fridge door)

Opened: room temp x 28 days o Detemir, Glargine U 300 < 30oC 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

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

Dizzy, light headed

Palpitations, sweating, anxiety

Hunger

Nausea, headache

Tingling, blurred vision

Difficulty concentrating

Confusion

Changed behavior

Drunk-like behavior

Trouble speaking

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

3-4 dextrose tabs

15 mL (3 packets) table sugar or honey

175 mL juice or regular soft drink

6 lifesavers

20 gm fast acting carbs

7 dextrose tabs

250 mL juice or regular soda

4 tsp sugar

8 lifesavers

Inject 1 mg glucagon SC or IM and call emergency services

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

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

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 4.0 – 4.9, safe to drive once BG ≥ 5 NEED TO RE-CHECK BG EVERY 4 H OF CONTINOUS DRIVING (and carry simple carb snacks)

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

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 90o 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

lecture 40 and 41 therapeutics of dm2 cooke/dossa … · screen every 3 years if ≥ 40 or high...

Documents