Type 2 Diabetes Treatment
Insulin treatment management
- Always look for *trends* (Don't go by one reading alone - *3 consecutive days*) - Adjust for *LOWS FIRST* (most worried about hypoglycemia! look for lows first) - Adjust for *high levels next* - Fasting levels - Adjust *one insulin at a time - (some exceptions)* - After adjustment: see if this improves other readings over a 3 day period (*give it 3 days to see results*) -Adjustment rule of thumb (can vary between clinicians) If insulin dose is: - Less than 8 units, adjust by 1 unit - Between 8-20 units adjust by 2 units - Greater than 20 units adjust by no more than 10% -When interpreting trends and *adjusting sugar readings*: NOTE: -what time they were taken (are they pre-meal or post-prandial readings) typically: pre-meal: 4-7 mmol/L, 2-hrs post-prandial: 5-10 mmol/L -which insulin dose is reflected in that reading -what factors may be influencing it (medications, exercise, changes in diet?) remember, trends! if single high reading, more likely to be other factors of changes in food or exercise etc -Regarding the insulin dose reflected in the reading: -Need to know how many doses they take per day and what time they take it and what kind it is (it changes based on that) -eg. one has 2 injections per day, breakfast and dinner; each injection: rapid/regular + intermediate (eg. NPH): their pre-breakfast test would reflect dinner NPH; pre-lunch test would reflect morning rapid; pre-dinner test would reflect morning NPH; bedtime test would reflect dinner rapid -eg. one has 4 injections per day, breakfast, lunch, dinner rapid + bedtime long-acting (glargine): their pre-breakfast would reflect long-acting glargine, their pre-lunch/dinner/bed-time would reflect rapid dose at breakfast/lunch/dinner respectively. -see lecture slides for cases -eg of an exception in adjusting one insulin at a time -suppose one injects rapid and NPH pre-breakfast and pre-dinner and the post-dinner readings are low (8 pm) but pre-dinner readings are high (6 pm) -so the 6pm reading reflects morning NPH; the 8pm reading reflects dinner rapid dose --> treat low first (nighttime reading low is especially dangerous: daytime hypoglycemia, can deal with it but if happens while sleeping, is dangerous) -Therefore we want to decrease dinner rapid dose and increase morning NPH (adjusting 2 at a time because after adjusting the morning NPH, the reading for 6pm would go down into normal range (say 6, which was 16 before) but the reading at 8pm (before any adjustment) was based on the pre-dinner bolus dose which brought the sugar level down (from say 16 to 5 the day before), so if we keep the pre-dinner bolus the same as before, we may run into hypoglycemia! we want to be decreasing the dinner bolus dose at the same time while increasing morning NPH to avoid hypoglycemia. *-Adjusting for Exercise* -Can cause *blood glucose to decrease several hours after exercise* -Monitor before, during and after exercise until pattern observed -Adjust insulin that will have the most impact at the time of exercise (eg. Morning NPH will need to be decreased for an afternoon golf game) -How much? general guidelines: Adjust insulin by - 10% for light activity - 20% for moderate activity - 30-40% for vigorous activity - If using rapid acting insulin and strenuous exercise is planned within 2hrs of injection, reduce the dose by 50% NOTES: -important: ask those detailed questions! if a patient calls and asks what to do when their sugar level is at 20. How much insulin is working right now? how long has it been before you last eat? When was their last insulin dose? What type of insulin is it? (they might have taken their basal insulin 15 mins ago, you need to ask the questions!) what other medications did you take? maybe suggest go exercise to bring it down etc, not black and white -insulin prescriptions are easily mistaken: take note: the U can be seen as a zero. always rationalize and counsel (what should be the normal initial starting dose? does the dose sound like what the doctor advise them? -COUNSEL ON HYPOGLYCEMIA (RECOGNITION AND TREATMENT) -esp for those with sulfonylurea, meglitinides, insulin -for all the first month of therapy and during dose increases -note the different treatment for those on acarbose -Definition of hypoglycemia: blood glucose < 4mmol/L -Exact level at which symptoms will occur will vary from patient to patient *Signs and Symptoms KNOW* -*Sweating, tremor, tachycardia, irritability,headache, hunger, nausea, tingling, blurred vision, dizziness, anxiety* - *Nocturnal: nightmares, restless sleep, sweating, morning headache* -ask patients what their symptoms are, it varies for individuals -Beta-blockers may mask the symptoms of hypoglycemia except for sweating (cholinergically-mediated) - need to inform patients of this -Review possible causes: -Delayed meal (are they taking medication with food?) -Increased activity -Gastroparesis (condition of abnormal stomach muscle motility and slow stomach emptying) -Excessive antihyperglycemic therapy -Drug interactions -Alcohol (increase sugar level due to caloric intake but decreases hepatic gluconeogenesis may cause hypoglycemia! may be hard to tell whether one is drunk or hypoglycemic. diabetics can drink but moderately 1-2 drinks is ok but WITH MEAL to avoid hypoglycemia) -Was the right insulin used? -Was the right dose used? *Treatment* - 15-20g carbohydrate - Measure blood glucose in 15 minutes - Repeat step 1 if blood glucose is still < 4 mmol/L - The 15g carb will only last them for a short period of time. Once hypoglycemia corrected follow with usual meal/snack (within 1 hour). If a meal is >1hr away snack with 15g carbohydrate+protein source example of 15g carbohydrates - 3/4 cups of Orange juice - 3 tsp or 3 cubes of Sugar - 6 pieces Lifesavers® - 3 pieces of 5g Glucose tablets* - 1 cup of Milk* - 1 tablespoon (15 ml) of Honey* (*=treatment for if one is on acarbose) - Glucagon used in unconscious patients -Note that chocolate bar shouldn't be used as treatment unless if that is the only thing available, because its absorption is slow: due to the fat content, slow gastric emptying Counsel on: -Safe blood glucose for driving (5 or >5 mmol/L): -esp for long distance truck drivers and those prone to hypoglycemia -if BG <5 mmol/L - take 15g of carbohydrates - check again in 15 mins - if BG >5 for 45 mins—> safe to drive - check BG every 4 hours of driving and carry simple carbohydrate snacks
Type 2 diabetes MONITORING
-A1c: generally every 3 months (glycemic target being met/adjusting treatments). Every 6 months when under controlled (stable at glycemic target) -look for trends (it's a marker of progression), take note of increasing of a1c and decreasing of a1c (and intervene accordingly based on the reason) -what is a good A1c? (note that healthy adults normally have a1c 4-6%) according to the evidence: want most T2D patients to be at 7% but for some people, we want to target lower than 7, some above 7 -generally the evidence from trials show that intensive glucose control may increase or decrease risk depending on the type of patient and treatment (eg. intensive treatment decreases microvascular complications but not macrovascular until longer term observed. For those with high CV risk, intensive glucose control increased death) -eg. ≤ 6.5% may be considered for those at higher risk of retinopathy and nephropathy (while balancing that with the risk of hypoglycemia) -eg. 7.1%-8.5% may be considered for those with limited life expectancy (or older/frail individuals), coronary artery disease (at risk of ischemia), multiple-comorbidities, high level of functional dependency, hx of severe recurrent hypoglycemia, hypoglycemic unawareness, long-standing diabetes in which levels lower cannot be achieved with even with intensified treatment -Blood Glucose monitoring -what is the effect of monitoring blood glucose in T2D patients? -ESMON: well done Ireland study shows that self-monitoring of blood glucose has no effect on glycemic control in T2D (A1c, BMI, hypoglycemia, use of oral hypoglycemic agent) but higher depression scores -may want to monitor initially but not for the rest of their life, testing only in special situations when it would help determine patient's course of action: in situations of acute illness, increased risk of hypoglycemia, when using insulin injections, pregnant or planning, poorly controlled glucose levels -Current practice: Individualizing, let them know the best available evidence. -For people who have been measuring everyday for a while, may be challenging for them to cut down to not measuring at all; can suggest lower frequency of measuring. No point of testing if not going to do anything with the numbers -those who want to test: can test at different times of day; focused measuring not routine measuring. eg. hypoglycemia symptoms, Infection, travelling, stress, adjustment in medication, nutrition, exercising. -if a1c stable, can back off from those measurements -if decreasing a1c: may have lost weight, may be able to reduce medication, or may be experiencing hypoglycemia -if exp hypoglycemia: start testing to look at why it occurred and how to avoid it (eg. measure before breakfast and 2 hrs after breakfast on monday, before lunch and 2 hrs after lunch on tuesday, before dinner and 2h after dinner on wednesday--> do this for 2 weeks, look for trends of when is the worst control of glucose then focus on that meal, try different things with diet/portion control for that meal) note: doesn't have to be mon, tues, wed
Insulin-sensitizing agents-Thiazolidinediones (TZD)
-Another strategy for the treatment of T2D is not only to optimize glucose control, but also to treat insulin resistance. -These agents reduce fasting blood glucose by 2.2-3.3 mmol/L -reduce A1C by 1-1.5%. -Combination with insulin is not approved in Canada due to increased risk of fluid retention and CHF. -In fact, TZD not recommended as first-line therapy due to associated increased risk of edema (fluid retention and increased plasma volume), weight gain (increases subcutaneous fat, NOT visceral fat), fractures in women (bone loss and bone fractures) and concern regarding cardiovascular outcomes (increased risk of myocardial infarction and CHF). -SHOULD NOT BE SEEING IT OFTEN ANYMORE -Need to get the patient to sign CONSENT FORM before taking it (due to its CV risk) -takes 6-12 weeks before max effect SE: -*CV: increase plasma volume/edema: tell patients to report unusual weight gain, SOB, edema, weakness, fatigue* -also causes *weight gain* (3-5 kg) -*hepatotoxicity*: Measure LFTs at baseline, q2months x 1 year then periodically (clinical judgement). *D/C if ALT > 3 x normal, if bilirubin or symptomatic ( fatigue, N&V, abd pain, dark urine- important counselling point)* *Contraindications*: -CV disease -hepatic dysfunction -Do NOT use with insulin (D/C when initiating insulin) -MOA: -Selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARγ) which regulates transcription of insulin-responsive genes involved in production, transport and utilization of glucose and lipid metabolism (causing fat cells to differentiate and become many small fat cells esp in non-visceral fat depots (peripheral and subcutaneous) note that intraabdominal fat is insulin resistant). These receptors are also found in muscles (increase insulin sensitivity) -PPAR receptors are found in muscle, fat and liver. -These agents increase insulin sensitivity in muscle and adipose tissue and inhibit gluconeogenesis (principal effects are by lowering insulin resistance in peripheral tissue, but an effect to lower glucose production by the liver is also possible) -Improvement of insulin sensitivity decreases the levels of circulating insulin (and hence preserves beta-cell function). -Taken with/without meal. -Because their mechanism of action involves gene regulation, the blood glucose lowering effect starts in 2 weeks and can take up to 6-12 weeks to achieve maximum effect. -Do not cause hypoglycemia. -*Rosiglitazone (Avandia)* 2-8 mg. -*Pioglitazone (Actos)* 15-45 mg.
Insulin 3 categories of insulin • bolus, basal, premix
-Benefit: -Reduced microvascular complications -Reduced macrovascular complications (including death) upon follow up -Insulin: -hypoglycemia (must carry sugar with them all the time) -weight gain Insulin + oral agent - Slow introduction to insulin (start with one injection) - Smaller insulin dose - Less hypoglycemia - Reduce weight gain associated with insulin Initiation: - 3 principles of insulin dosing • Your starting dose will be wrong • Titrate dose • No maximal dose of insulin -The most common regimen: *Basal insulin once daily* *-5 to 10 units s.c.of basal daily at bedtime* *-Increase dose by 1 unit daily until fasting in AM at target* -Continue oral medications -D/C thiazolidinediones: Rosiglitazone (Avandia) Pioglitazone (Actos) -Check A1c q3months-- Expect a downward trend to < 7%
Meglitinides *Repaglinide*
-Benefits -reduce A1c by 1-1.5% -No long-term studies in people with diabetes -MOA: These agents are potent insulin secretagogues; acts via closure of ATP-sensitive potassium channels. -They have a pharmacologically distinct binding profile on a site close to the potassium channel. They provide potent but *glucose-dependent release* from β-cells (does not result in release of insulin from the β-cell in the absence of glucose) after closure of ATP sensitive potassium channels. -->Improves a primary pathophysiological impairment: insulin secretion -They mimic physiological insulin secretion and restore first- phase insulin response and blunt postprandial -SE: -hypoglycemia -weight gain (up to 2kg) -These are non-sulfonylurea oral hypoglycemic agents (thus useful in patients with sulfa allergies). -they are associated with less hypoglycemia when and if a meal is missed. -*Fast onset, short duration*. hyperglycemia. -Requires TID to QID dosing. -0.5-16 mg depending on HbA1c. -*Taken before the first bite or 15-30 min prior to a meal*.
Biguanides Metformin (Glucophage)
-First line of treatment for people with T2D. -Benefits: -reduce microvascular and macrovascular complications and death (10-yr-study) -reduce A1c by 1-1.5% -improve insulin resistance -does not provoke hypoglycemia (safe to take at bedtime) -Is an insulin sparing agent, does not increase body weight (but weight loss ~3kg/4 yrs) (Note: Unlike sulfonylureas and Repaglinide/Nateglinide, these drugs do not act on the β-cell and do not affect insulin secretion. They can be considered as being euglycemic, not hypoglycemic, even in large doses. They require some insulin secretion. Have a long record of relative safety) Possible MOA: Exact mechanism of action unknown. -Improve a primary pathophysiological impairment of diabetes - insulin resistance. -They act either directly through their ability to activate AMPK (AMP activated protein kinase) or indirectly to enhance insulin signaling. SE: -*Taken with meals to minimize gastrointestinal side effects*. Dose related GI side effects include *diarrhea*, metallic taste, nausea, anorexia, tend to occur at the *onset of therapy, and are often transient (2-3 wks) and dose-related*. -Very rare - lactic acidosis (likely a result of intestinal anaerobic glucose metabolism leading to excess lactate formation; weakness, abdominal pain, hyperventilation (heavy laboured breathing) malaise, drowsiness, abdominal distress )--> timing of the symptoms is important, if experience these when medication just started, prob SE associated with the med but if after taking it for awhile, lactic acid may have built-up Contraindications: - *renal impairment* (metformin is excreted by the kidney, if not properly excreted, build up can cause lactic acidosis) - eGFR < 60ml/min caution - eGFR < 30ml/min contraindication - elderly until renal function known - hepatic disease - history of lactic acidosis - *Excessive alcohol (Acute or chronic)* (alcohol can affect the liver which is a good source of getting rid of lactate and preventing lactic acidosis) - pyelography, angiography (can cause acute renal failure, hold before and 48h after procedure) - septicemia, dehydration, hypoxemia (stop/hold metformin when experiencing vomiting and diarrhea (which causes dehydration) until resolved--> can cause lactic acidosis) eg dehydration can cause the kidney to shut down and metformin not excreted therefore lactic acid build up Dose: -Start low and increase slowly (minimize GI) -250mg-500mg with main meal and increase by 250mg-500mg increments weekly if needed -Usual dose = 1g po bid (max dose) -Decreases in fasting blood glucose *seen within 3-5 days, maximal effects within 1-2 weeks* -The only biguanide available in Canada at present is Metformin. However many other generics present. -250-2500 mg -Also available in combination with Sitagliptin, a DPP-4 inhibitor (Janumet) with Rosiglitazone with a TZD (Avandamet).
Incretins *Glucagon-like peptide-1 (GLP-1) analogues* INJECTABLE
-Glucagon like peptide (GLP-1) secreted from the intestinal L-cells has multiple effects that include: a) effects on the hypothalamus (decreased appetite) b) effects on the stomach (to decrease gastric emptying) c) effects on the liver (direct and indirect to lower glucose production) and muscle (to indirectly stimulate glucose uptake) d) effects on the pancreas (to increase glucose dependent insulin secretion (main effect), decrease glucagon secretion and increase beta cell number by increasing their formation and decreasing their demise) -*Decreases A1C by 0.8-1.5%* -Although injected, these drugs are gaining in popularity not only due to their control of blood glucose (effective in A1C lowering but rare hypoglycemia) but also due to their ability to *promote weight loss* (anorexia; 2.4-4 kg after 1 year of use). -It should be noted that GLP- 1 is degraded by dipeptidyl peptidase-4 (DPP4). Because of this, GLP-1 has a short half-life (only 2 minutes). -SE: -mild to moderate nausea (improves over time), vomiting and diarrhea -pancreatitis (under investigation) -contraindication: those with family history of thyroid cancer (seen in rats) -*Exenatide (Byetta)* -First injectable (subcutaneous) incretin therapy to become available for the treatment of diabetes. -10-20 μg (start with 5 mcg) *injected less than 60 minutes before the two main meals (the 2 meals at least 6 hrs apart: breakfast and dinner)* *BID injectable* -Do not administer after a meal -*Take other medications one hour before injecting exenatide (If the medication is taken with food, take with snack)* -May need to reduce dose of sulfonylurea by 50% -also available in *weekly injectable* -Exenatide is a synthetic exendin-4 that is a DPP- IV resistant GLP-1 analog. This explains the longer duration of pharmacologic effects observed with Exenatide. (Exendin-4 is a protein isolated from the saliva of the Gila monster. It exhibits approximately 50% sequence identity with that of the mammalian incretin glucagon-like peptide-1 (GLP-1)) -Contraindications: Creatinine clearance < 30 ml/min, Severe GI disease - gastroparesis (paralysis of stomach: neuropathy associated with stomach, may be SE of diabetes) -SE: causes significant nausea (but decrease with time and is dose dependent) -pancreatitis? -anti-exenatide antibody titre (clinical significance?) -*Liraglutide (Victoza)* -Long acting *(once daily injectable)* 0.6-1.8 mg. -DPP-4 resistant GLP-1 analog. -Substitution of Lys34 with Arg34 and addition of a C-16 fatty acid (palmitoyl) at position 26 (lysine). -This *increases albumin binding, thus reducing renal clearance and slows degradation by DPP-IV*. -Similar side effects to Exenatide. -Start with 0.6mg daily x 1 week to reduce GI symptoms then increase to 1.2mg sc daily. Can increase up to 1.8mg sc daily -*store in fridge, after initial use, it can be stored at room temperature x 1 month (or in fridge)* -Mild renal insufficiency - CrCL50-80mL/min-No dose adjustment. CrCl lower than that monograph: do not use, studies: dose adjustment prob not needed -*contraindication*: in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (cause thyroid cancer in rats) -suggest monitoring: -*Report mass in neck, Dysphagea, Dyspnea, Persistent hoarseness* -Unknown if serum calcitonin monitoring or thyroid ultrasound may lower the risk -*Albiglutide (Eperzan)* -30-50 mg *Once weekly* -Half-life 4-7 days, which is longer than the other two GLP-1 analogs. -*Dulaglutide (Trulicity)* -*weekly injectable* -SE: -Reduced blood pressure -Increased heart rate (Clinical significance?) -n,v,d
SGLT-2 Inhibitors
-In subjects with normal kidney function and glucose tolerance, glucose homeostasis in the body is such that there is net 0 g/day excreted. Virtually all filtered glucose is reabsorbed back into the blood stream in the proximal tubule. -*The majority (90%)* of renal glucose reabsorption takes place in the *convoluted segment (S1)* of the proximal tubule where the *low-affinity, high-capacity sodium- glucose transporter (SGLT) 2* and the glucose transporter *(GLUT) 2* are located. -*The remaining 10%* is reabsorbed in the *distal straight segment (S3)* of the proximal tubule where the *high-affinity, low-capacity SGLT1 transporter*, and *GLUT1*, are located. -This variation is thought to allow the majority of glucose to be reabsorbed in the S1 segment of the proximal tubule, whereas any glucose that is left in the ultrafilterate by the time it reaches S3 is avidly absorbed. -SGLT2 has a sodium:glucose co-transport ratio of 1:1, while -SGLT1 has a sodium:glucose co-transport ratio of 2:1. -SGLT inhibition reduces the glucose reabsorption capacity of the renal tubule, leading to a decrease in the RTG (renal threshold of glucose--the blood concentration at which glucose is excreted) and the appearance of glycosuria. -When blood glucose levels exceed 10 mmol/L, the capacity of the SGLT inhibitors is saturated and glucose is excreted into the urine. (RTG is 10-11 mmol/L in healthy subjects) -Appreciable urinary glucose excretion occurs only when plasma glucose exceeds RTG. -*Reduces A1c by 0.7-1%* -SGLT2 inhibition with Canagliflozin lowers RTG promoting renal glycosuria. -There is loss of about 80-100 grams of glucose/day (approximately 3-4 g/h) in subjects with T2D. -This is a loss of "caloric equivalents" of approximately 300-400 cal/day. -There is substantive decrease in net glucose entering system - so lowers plasma glucose. -SE: -Low risk of hypoglycemia. -Two other effects that may be of benefit to patients with diabetes include *weight loss and a small reduction in blood pressure*. -The most commonly reported adverse reactions during treatment include *urinary tract infections and genital yeast infections* -Also hypotension and lowered intravascular volume. -*Diuretic, therefore ↑ risk of dehydration* -? Diabetic ketoacidosis -? Fractures -be careful in elderly esp those on diuretics (choose other options) -*Renal function*: Invokana: Contraindicated if eGFR < 45 ml/min; do not start if eGFR < 60 ml/min Forxiga: Contraindicated if eGFR < 60 ml/min Jardiance: Contraindicated if eGFR < 45 ml/min -Do not combine with thiazolidinediones-pioglitazone (bladder cancer risk?) -*Canagliflozin (Invokana)* 100 mg once daily -*Dapagliflozin (Forxiga)*. 5-10 mg/daily -*Empagliflozin (Jardiance)* 10 mg/daily (*this is the one in the study that shows CV outcome benefit*--> use the one in the study) -Take prior to your first meal (with or without food) *Take in the morning* except Forxiga can be taken at anytime of day -Careful of dehydration and low blood pressure: *Drink lots of water especially during first 30 days especially in people who are on ACEI or ARB or lower blood pressure* -*Monitor potassium* especially those on ACEI/ARB or potassium sparing diuretic
Incretins Dipeptidylpeptidase-4 (DPP-4) inhibitors
-MOA: -DPP-4 is an enzyme that causes rapid degradation of GLP-1. Its inhibition results in increased circulating levels of GLP-1, hence prolonging the action of GLP-1. -Increase concentration of GLP-1 and GIP -Increase insulin release -Decrease glucagon release -Decrease A1C by 0.4-1.0%. -SE: nasopharyngitis (inflammation of the nasal passages), upper respiratory infections, and headaches, nausea, diarrhea, arthralgias -Pancreatitis? (being investigated, don't know if it's from diabetes or from the medication) -Weight neutral -Rare hypoglycemia *Sitagliptin (Januvia)*. -100 mg daily -50mg po daily (eGFR 30-50ml/min) -25mg po daily (eGFR <30 ml/min) -79% excreted unchanged in the urine -Taken in the morning, with or without food -no increase risk of heart failure (2015) *Saxagliptin (Onglyza)* -eGFR > 50ml/min - 5mg po daily -eGFR < 50ml/min - 2.5mg po daily -associated with the most drug interactions: Metabolized via cytochromeP450 3A4/5 -Increased saxagliptin levels with diltiazem and ketoconazole? Reduced saxagliptin levels with rifampin -covered by pharmacare -increased risk of heart failure (2013: prob not going to see much of it anymore) *Linagliptin (Trajenta)* -5 mg once daily. -advantage: no adjustment for renal dysfunction -still do not use in severe impairment -Hypersensitivity reactions. *Alogliptin (Nesina)* -25 mg once daily -12.5 mg daily if CrCl ≥30 to <60 mL/min -6.25 mg once daily if CrCl ≥15 to <30 mL/min -ESRD (end-stage renal disease) (CrCl <15 mL/minute or requiring hemodialysis): 6.25 mg once daily; administered without regard to timing of hemodialysis -Severe stomach/abdominal/back pain, headache, upper respiratory tract infection. -Vomiting -Peripheral edema • Anemia -Neutropenia -no increase risk of heart failure
TD2 treatment approach
-The first line of treatment of T2D is a program of diet, exercise and lifestyle modifications (for 2-3 months first) -NUTRITION. 3-5% weight reduction significantly improves glycemic control. (plate method or hand method) eg. choose grains/starch, fruit like the size of a fist, 2 kinds of vegetables--the amount you can hold with both hands, limit fat to the size of the tip of your thumb, choose meat/protein--the size of your palm. drink up to 250 ml of low fat milk. -EXERCISE. moderate to vigorous-intensity Aerobic exercise preferred. 30 minutes of brisk walking, 5 times a week (include resistance exercise at least 2 times/wk). Benefits appear to result from enhanced insulin sensitivity and increased glucose uptake in muscle and other tissues. (be sure to assess the patient's health before prescribing exercise regimen, can work up to this target) -If a patient's A1C < 8.5%: Start metformin OR lifestyle modifications (diet + exercise) then reassess in 2-3 months then decide on starting metformin -if a patient's A1C is ≥8.5 %: Start metformin AND Consider combo therapy to achieve ≥1.5% A1C reduction -if symptomatic hyperglycemia and metabolic decompensation (Polyuria, Polydipsia, Weight loss, Volume depletion)--> concern about insulin deficiency: initiate insulin +/- metformin -if after metformin, still not at glycemic target, Add another agent best suited to the individual by prioritizing patient characteristics (2nd line: up for debate, eventually lead to insulin) -Priority patient characteristic is clinical cardiovascular disease --> suggest SGLT2 inhibitor with demonstrated CV outcome benefit (or Victorza (Liraglutide), a study has been published just recently regarding its effect on the CV outcomes) -patient characteristics to consider: Degree of hyperglycemia, Risk of hypoglycemia, Overweight or obesity, Cardiovascular disease or multiple risk factors, Comorbidities (renal, CHF, hepatic), Preferences & access to treatment -for choice of agents also consider: Consider relative A1C lowering, Rare hypoglycemia, Weight loss or weight neutral, Effect on cardiovascular outcome, See therapeutic considerations, consider eGFR See cost column; consider access -note that diabetes is a progressive condition, it is common that patient would need additional therapy as time goes on: -Within 3 years, 50% required combination therapy -Within 9 years, 75% required combination therapy note that: use of insulin in T2D patients is when diabetes cannot be controlled by diet/exercise or other medications (and progressive deterioration of beta-cell function means that individuals with T2D will also become insulin-deficient and require insulin therapy)
Drugs: Sulfonylurea
-There are two generations of sulfonylureas; 1st generation is less potent than 2nd generation (which are 1000x more potent). 2nd generation SU are preferred, due to their increased effectiveness and decreased side effects. -Benefits: -reduce microvascular complications (10 yr-UKPDS trial) and upon follow up (another 10 yr) reduce macrovascular complications and death -reduce A1c by 1-1.5% -SE: -*Hypoglycemia*: may be prolonged and more severe than with insulin (generally more prone to hypoglycemia because can release insulin even when not eating) *therefore NOT administered at night* (hard to distinguish hypoglycemia and sleeping) and use with caution in the elderly, renal dysfunction, irregular meals and under certain stress conditions (eg. severe infections, trauma or surgery) -*Weight gain*: problem in obese patients -*Allergic reaction*: cannot use if allergic to sulfa compounds -MOA: -Binds to receptor at surface of β-cells--the Sulfonylurea receptor on β-cell is coupled to an ATP- sensitive K+ channel in the plasma membrane. Binding to the receptor causes closing of the K+- ATP channels, depolarization of the membrane which opens voltage-dependent Ca2+ channels. Increased Ca2+ in the cell triggers movement of insulin granules to the cell surface, where contents (i.e., insulin) are released into circulation. These drugs act in a manner similar to that seen with glucose. -50% of patients lose effectiveness in 5 years *Glyburide (Diabeta)*: -Most commonly used SU. -2.5-20 mg/day. -*Administered with breakfast or the first main meal* -It is metabolized in the liver (and hence is *contraindicated in the presence of hepatic impairment*) -its elimination is 50% renal and 50% feces. -*Slower onset* (hence less desirable for the short term elevation in glucose after a meal) *but longer duration* (and hence may be beneficial in controlling glucose during the night and/or throughout the day) *Gliclazide (Diamicron)* -80-320 mg/day. -*Taken with meals (breakfast or first meal)* -Metabolized in liver and eliminated in kidneys (*contraindicated when there is severe renal insufficiency*).. -Has a *rapid onset* (allows it to function much like the body's normal response to a meal when higher levels of insulin are required to deal with the increase in glucose) and *short duration of action* (hence won't cause too much hyperinsulinemia). -*Decreased incidence of hypoglycemia* compared to glyburide and is also associated with *less weight gain*. *Glimepiride (Amaryl)*: -1-8 mg/day. -*Taken with breakfast or first meal*. -Has a *rapid onset* and *long duration of action*. Because of this, it is effective in *controlling postprandial blood glucose with once-daily dosing*. -associated with *less hypoglycemia* than glyburide. -Associated with *less weight gain* -Eliminated 60% in urine, 40% in feces (and *can be used safely in mild to severe renal impairment*. *Tolbutamide* -A first generation agent, Tolbutamide is still available in Canada, but rarely used. -Should be used with *caution in patients with cardiovascular disease* (they influence the cardiac potassium channel).
Alpha-glucosidase inhibitors Acarbose
-These drugs are used in combination with other oral agents for patients whose glucose levels cannot be controlled with a single agent. -Benefit -With this drug, there is a modest drop in postprandial blood glucose by 2.2-2.8 mmol/L -reduce A1C by 0.5-0.8%. -no long-term studies in people with diabetes -MOA: -Aka "starch blockers" -Acarbose (blocks glucose absorption from the gut) is a reversible inhibitor of alpha-glucosidases (maltase, isomaltase, glucoamylase) in small intestine (a membrane bound enzyme of the intestinal brush border that slowly breaks down complex CHO into monosaccharides: starch, sucrose, maltose into glucose after a meal) Hence, the drug delays the digestion of carbohydrates, the absorption of glucose in the small intestine and prevents glucose surges that commonly occur after eating -(only monosaccharide's such as glucose and fructose can be transported out of the intestinal lumen and into the bloodstream). -Improved postprandial control. -SE: -GI distress (flatulence, diarrhea, cramps) is an adverse effect - minimized by starting at low doses (eg. Start with 25mg daily and increase by 25mg/meal increments gradually over 6-8 weeks) -Flatulence is the most common complaint and occurs as a result of fermentation of unabsorbed carbohydrate, as it sits longer in the large intestine. -GI symptoms may improve with continued therapy -Does not cause weight gain and has a low or no incidence of hypoglycemia. However, if hypoglycemia does occur, (counsel!! esp for those taking other diabetes meds that may cause hypoglycemia) treat only with pure glucose (eg. Glucose tablets (15 grams), Milk (1 cup 250mL), Honey (1 tablespoon)) and not sucrose (table sugar) whose breakdown may be blocked prolonging the duration of hypoglycemia. -the usual starting dosage of GLUCOBAY is 50 mg given orally once daily. After 1-2 weeks, the dosage should be increased to 50 mg b.i.d. with a subsequent increase to 50 mg t.i.d. -Taken with first bite of meal to be effective.
Anti-Obesity drug
For obesity (start with life style modifications first then pharmacotherapy then surgery) pharmacotherapy: orlistat -prevents fat digestion and absorption by binding to GI lipases -excreting out triglyceride -TG not turned to FA and not packaged to micelles, not absorbed -significant drop in body weight
