LONG TERM BENEFITS OF ORAL AGENTS

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LONG TERM BENEFITS OF ORAL AGENTS. J. Robin Conway M.D. Diabetes Clinic Smiths Falls, ON www.diabetesclinic.ca. Long Term Benefits of Oral Agents. Robin Conway M.D. Physical Activity and Diabetes. - PowerPoint PPT Presentation

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  • LONG TERM BENEFITS OF ORAL AGENTSJ. Robin Conway M.D.Diabetes ClinicSmiths Falls, ONwww.diabetesclinic.ca

  • Long Term Benefits of Oral AgentsRobin Conway M.D.

  • Physical Activity and DiabetesFor people who have not previously exercised regularly and are at risk of CVD, an ECG stress test should be considered prior to starting an exercise programTesting is particularly important before, during and for many hours after exercise.

    Type

    Recommendation

    Example

    Aerobic especially type 2

    150 minutes of moderate-intensity exercise each week

    spread out over at least 3 non-consecutive days

    gradually increase to 4 hours or more a week

    sessions should be at least 10 minutes at a time

    Brisk walking

    Biking

    Raking leaves

    Continuous swimming

    Dancing

    Water aerobics

    Resistance all persons with diabetes, including elderly

    3 times a week

    start with 1 set of 10-15 repetitions

    progress to 2 sets of 10-15

    then 3 sets of 8

    Weight lifting

    Exercise with weight

    machines

  • Nutrition TherapyPeople with diabetes should:Receive nutrition counseling by a registered dietitianReceive individualized meal planningFollow Canadas Guidelines for Healthy EatingPeople on intensive insulin should also be taught to adjust the insulin for the amount of carbohydrate consumed

  • Pharmacologic Management of Type 2 DiabetesAdd anti-hyperglycemic agents if:Diet & exercise therapy do not achieve targets after 2-3 month trialOr newly diagnosed and has an A1C of 9%Intensify to reach targets in 6-12 months

    A1C& BMISuggested starting agent< 9%BMI 25Biguanide alone or in combinationBMI < 251 or 2 agents from different classes 9%--2 agents from different classes or insulin basal and/or preprandial

  • Management of Hyperglycemia in Type 2 Diabetes Patients

  • Oral Agents for Type 2 DiabetesCombination at less than maximal doses result in more rapid improvement of blood glucoseCounsel patients about hypoglycemia prevention and treatment

    SMBG is recommended at least once daily

    Class

    Expected decrease in A1C with monotherapy

    lpha-glucosidase inhibitor

    0.5 0.8

    Biguanide

    1.0 1.5

    Insulin

    Depends on regimen

    Insulin secretagogues

    1.0 1.5

    0.5 for nateglinide

    Insulin sensitizers (TZDs)

    1.0 1.5

    Combined rosiglitazone and metformin

    1.0 1.5

    Antiobesity agent (orlistat)

    0.5

  • Targets for Glycemic Control* Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors

    To achieve an A1C 7.0%, patients should aim for FPG, preprandial and postprandial PG targets

    A1C

    (%)

    FPG/preprandial (mmol/L)

    2h Postprandial (mmol/L)

    Target for most patients

    ( 7.0

    4.0 7.0

    5.0 10.0

    Normal range

    (if it can be safely achieved)

    ( 6.0

    4.0 6.0

    5.0 8.0

  • Burden of Poor Control - Cost

  • Burden of Poor Control - CostEstimate annual cost to health plans by level of glycemic control

    Determine effect of Improved Glycemic Control on Health Care Utilization and Costs

  • Oral Antihyperglycemic Agents: BiguanidesDecreases hepatic glucose production, enhances peripheral glucose uptake

    May reduce insulin resistance in the peripherye.g., Metformin Contraindicated in renal/hepatic insufficiency May cause GI side effectsNot associated with hypoglycemia, may promote weight lossMeltzer et al CMAJ 1998;159(Suppl):S1-29.MUSCLELIVER

  • Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs)Decrease insulin resistance

    Increase insulin-dependent glucose disposal, decrease hepatic glucose productione.g., Pioglitazone, rosiglitazonePioglitazone has a positive effect on lipidsNot associated with hypoglycemiaPossible URI, headache, edema, weight gain and reduction in hemoglobinPlosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.MUSCLEADIPOSE TISSUELIVER

  • Thiazolidinediones: Mechanism of Insulin SensitizationINSULINRECEPTORRNADNASaltiel, Olefsky Diabetes 1996;45:16619.PPARINSULINGLUT-4GLUCOSE

  • Durability of Glycemic Control with Pioglitazone Long TermEinhorn D et al. Diabetes 2001;50 (suppl2):A111HbA1c (%)

  • Metformin & Pioglitazone Study - Open Label ExtensionChange in HbA1c (%)Change in fasting glucose (mmol/L)Einhorn et al. Clin Therapeutics 2000;12:1395-1409

  • Oral Antihyperglycemic Agents: SulfonylureasStimulate pancreatic insulin release

    e.g., First-generation: tolbutamide, chlorpropamide, acetohexamidee.g., Second-generation: Glyburide, gliclazideSecondary failure a problemWeight gain, risk of hypoglycemiaMeltzer et al CMAJ 1998;159(Suppl):S1-29.PANCREAS

  • Natural History of Type 2 DiabetesHenry. Am J Med 1998;105(1A):20S-6S.

  • Oral Antihyperglycemic Agents: Alpha-glucosidase inhibitorsSlows gut absorption of starch and sucrose

    Attenuates postprandial increases in blood glucose levelse.g., Acarbose GI side effectsNot associated with hypoglycemia or weight gainSalvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.INTESTINE

  • Oral Agents for Type 2 DiabetesCombination at less than maximal doses result in more rapid improvement of blood glucoseCounsel patients about hypoglycemia prevention and treatment

    SMBG is recommended at least once daily

    Class

    Expected decrease in A1C with monotherapy

    lpha-glucosidase inhibitor

    0.5 0.8

    Biguanide

    1.0 1.5

    Insulin

    Depends on regimen

    Insulin secretagogues

    1.0 1.5

    0.5 for nateglinide

    Insulin sensitizers (TZDs)

    1.0 1.5

    Combined rosiglitazone and metformin

    1.0 1.5

    Antiobesity agent (orlistat)

    0.5

  • Natural History of Type 2 DiabetesHenry. Am J Med 1998;105(1A):20S-6S. Lifestyle

    Metformin/ThiazolidinedionesSecretagogues

  • Targets for Glycemic Control* Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors

    To achieve an A1C 7.0%, patients should aim for FPG, preprandial and postprandial PG targets

    A1C

    (%)

    FPG/preprandial (mmol/L)

    2h Postprandial (mmol/L)

    Target for most patients

    ( 7.0

    4.0 7.0

    5.0 10.0

    Normal range

    (if it can be safely achieved)

    ( 6.0

    4.0 6.0

    5.0 8.0

    I would like to see a chart prior to this slide see the page entitled Physical ActivityI think this could replace this slideAnna let me know what you think about changing to a table insteadCan remove the last columnSee flipchart pharmacological management of type 2, I like the simple chart as well describing A1CNeed to replace or add a different title such as Get to TargetquicklyUnder Normal range please change to if it can safely be achievedI would suggest removing the recommendation, however mentioning #1 under the chartThe socioeconomic buden of diabetes can be documented in different ways:

    Burden of poor control established by assessing the relationship between glycemic control and diabetes health care costExample of such a study is given above where Gilmer et al. Estimated the cost to health plans associated with different levels of glycemic control

    Lack of control in diabetes has a socioeconomic burden for all stakeholders in health careThe socioeconomic buden of diabetes can be documented in different ways:

    Burden of poor control established by assessing the relationship between glycemic control and diabetes health care costExample of such a study is given above where Gilmer et al. Estimated the cost to health plans associated with different levels of glycemic control

    Lack of control in diabetes has a socioeconomic burden for all stakeholders in health careOral Antihyperglycemic Agents: BiguanidesThe biguanide, metformin (Glucophage) has no effect on endogenous insulin secretion. Its mechanism of action is not completely clear, but it is thought to act primarily to decrease hepatic glucose production and enhance insulin-mediated glucose uptake.1,2 Metformin may reduce insulin resistance by enhancing the effect of insulin on peripheral receptor sites. Metformin has been shown to decrease fasting glucose, glycosylated haemoglobin (HbA1C), fasting triglycerides, and total and LDL-C levels, and to increase HDL-C levels.2 Clinical trials with both diet and sulfonylurea-failure patients have demonstrated a further decrease HbA1C levels of 1.5-2% with the addition of metformin. Metformin is contraindicated in patients with renal insufficiency, hepatic disease, cardiac insufficiency, alcohol abuse, any hypoxic condition, or a history of lactic acidosis.2,3 Side effects include mild self-limiting diarrhea, nausea or anorexia and some patients have complained of a metallic taste. The only major systemic side effect is lactic acidosis. Metformin does not cause hypoglycemia when used alone, and it may promote weight loss.

    References: 1. Meltzer S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-S29. 2. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:445-500. 3. Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54:355-68.Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs)Key message: Thiazolidinediones decrease insulin resistance and pioglitazone may also positively effect lipid parameters.TZDs are the newest class of antihyperglycemic agents for type 2 diabetes and include rosiglitazone and pioglitazone. Troglitazone is no longer available due to concerns of hepatic toxicity. These agents enhance sensitivity to insulin in the liver, adipose tissue and muscle, which results in improved insulin-mediated glucose disposal.1,2 TZDs activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-), which is involved in adipose cell differentiation and insulin-mediated glucose uptake in peripheral tissues. They reduce the expression of leptin (a signalling factor that regulates appetite, body weight and energy balance), and increase the expression of a lipid binding protein that plays a key role in the facilitated transport of glucose into adipocytes and skeletal muscle.1,2Studies have demonstrated a dose-dependent reduction of HbA1C, fasting blood glucose and plasma insulin levels. Pioglitazone may also improve lipid abnormalities, particularly hypertriglycidemia.1Modest weight gain has been reported, but hypoglycemia is rare.1,2 Upper respiratory tract infections, edema, headache and reduction in hemoglobin have also been reported.1,2References: 1. Plosker GL, Faulds D. Troglitazone. Drugs 1999;57:410-32. 2. Balfour JA, Plosker GL. Rosiglitazone Drugs 1999;57:921-30. Thiazolidinediones: Mechanism of Insulin SensitizationThiazolidinediones cross the plasma membrane and pass through the cytoplasm to the nucleus where they bind with the nuclear receptors, peroxisome proliferator-activated receptor-gamma (PPAR-). These receptors are found in tissues involved in insulin action, including adipose tissue, skeletal muscle, and the liver. Activation of PPAR- nuclear receptors sends signals into the nucleus that augment the function and efficiency of insulins effect on transcription factor activation. This augmentation increases the nuclear based actions of insulin which include the signal for formation of proteins involved in enzymatic processes, cell growth, regulation of insulin receptor activity and glucose transport.1 TZDs, thus improve the cells insulin sensitivity by increasing the insulin signal in the nucleus, which results in an increased number of GLUT-4 transporters and increased glucose entry into the cell.Pioglitazone has also shown some activation of the PPAR- receptor, which has been linked to some aspects of lipid metabolism.2-4 This may account for pioglitazones beneficial effects on lipid parameters.

    References: 1. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996;45:1661-9. 2. Lehmann JM, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR-). J Biol Chem 1995;270:12953-6. 3. Forman BM, et al. 15 deoxy-12,14 prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-. Cell 1995;83-803-12. 4. Henry RR. Thiazolidinediones. Endocrinol Metab Clin North Am 1997;26:553-73.The durability of pioglitazone to maintain improved glycemic control was demonstrated by a sustained reduction in the HbA1c of 1.39% (mean change from baseline) throughout the 72 week follow up period.In an open label extension to the double blind study, further reductions in HbA1c and fasting plasma glucose were observed. Patients treated with pioglitazone and metformin for 72 weeks had mean changes from baseline of 1.4% in HbA1c and 3.5 mmol/L in fasting plasma glucose. Oral Antihyperglycemic Agents: SulfonylureasSulfonylureas include the first generation compounds: acetohexamide(Dimelor), chlorpropamide (Diabinese), and tolbutamide (Orinase), and the second-generation compounds, glyburide (DiaBeta), and gliclazide (Diamicron). These agents work primarily by stimulating pancreatic release of insulin.1 This reduces hepatic glucose output and facilitates peripheral glucose disposal.First generation and second generation compounds have similar efficacy, but the second generation drugs are more potent on a per milligram basis, tend to produce fewer side effects, interact less frequently with other drugs and allow for once a day dosing.2HbA1C levels can be reduced by 1-2% in responsive patients, but only 60-70% of patients achieve glycemic targets.3 Patients with high fasting blood glucose levels and severe obesity often respond poorly to these compounds. About 5-10% of patients/year exhibit secondary failure to these agents.Most side effects are mild and infrequent, but one major complication of sulfonylurea agents is the potential to increase the occurrence of hypoglycemia.1-3 This has been more often associated with chlorpropamide and glyburide but all sulfonylureas have this adverse effect.3 Weight gain, sometimes of several kilograms, may occur and is undesirable in already overweight patients.3References: 1. Meltzer S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-S29 2. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:445-500. 3. Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54:355-368.Natural History of Type 2 DiabetesPrior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. Impaired Glucose Tolerance (IGT): However, at some point in time, either due to early -cell dysfunction or due to a natural limit of -cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached. Type 2 Diabetes: Follo...