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GO! Diabetes Train the Trainer Program

GO! Diabetes Train the Trainer Program. Glycemic Control – Oral Agents. Fed State Insulin Glucagon Incretins GLP-1 GIP Amylin. Fasting State Insulin Glucagon Incretins GLP-1 GIP Amylin. Metabolism 101. PANCREAS. GLUCAGON. GLUCAGON. GLUCAGON. AMYLIN. INSULIN. INSULIN.

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GO! Diabetes Train the Trainer Program

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  1. GO! DiabetesTrain the Trainer Program

  2. Glycemic Control – Oral Agents

  3. Fed State Insulin Glucagon Incretins GLP-1 GIP Amylin Fasting State Insulin Glucagon Incretins GLP-1 GIP Amylin Metabolism 101

  4. PANCREAS GLUCAGON GLUCAGON GLUCAGON AMYLIN INSULIN INSULIN How The Body Handles Glucose (Fed State) LIVER BRAIN Glucose 90-140 mg/dL Blood Glucose 60-90 mg/dL FAT GI TRACT MUSCLE

  5. PANCREAS GLUCAGON GLUCAGON GLUCAGON AMYLIN AMYLIN INSULIN INSULIN INSULIN GI TRACT Pathophysiology of Type 2 Diabetes LIVER Metformin (Glitazone) Insulin Sulfonylureas Insulin Analogs Glinides Exenatide BRAIN INSULIN INSULIN A1C < 7% Premeal ~ 100mg/dL PPG < 200 mg/dL Hyperglycemia FAT Weight Loss Exercise Glitazones (Metformin) Pramlintide Dietary Composition Portion Control -Glucosidase Inhibitors MUSCLE

  6. General Rules Hypoglycemic Therapy • Don’t forget lifestyle changes • Target the pathophysiology • Catabolic – increase insulin • Obese –attack insulin resistance • Multifactorial (most cases) –do both • Realize the need to add eventually add therapies • Predict what will be needed to reach glycemic goals

  7. General RulesHypoglycemic Therapy • Normalize fasting glucose levels first • Many patients will achieve glycemic targets • When to target postprandial glucose levels? • Preprandial values are at goal • A1C levels are not met • Measure 1-2 hours after beginning of the meal • Glucose are generally at their peak

  8. Glycemic Goals of Therapy Verbal Target ~100 <<200 As low as possible w/o unacceptable AE Goal Premeal plasma glucose (mg/dL) 2-h postprandial plasma glucose A1C ADA 90-130 <180* <7%** ACE <110 <140 <6.5% * Evaluation and treatment of postprandial glucose may be useful in the setting of suspected postprandial hyperglycemia, with the use of agents targeting postprandial hyperglycemia and for suspected hypoglycemia ** More stringent glycemic goals (i.e. a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia Diabetes Care 2007;30:S4-41

  9. Biguanides: Metformin Mechanism of action • Reduces hepatic glucose production • Depends upon presence of insulin Safety and efficacy • Decreases A1C 1-2% • Adverse effects: diarrhea and nausea; main risk: lactic acidosis • Discontinuation rate 5% • Contraindications: renal, cardiac, hepatic insufficiency; IV contrast • No direct effect on kidney Dosing • Initial dose: 500 mg once a day; dosing: usually BID • Maximum effective dose: 2,000 mg per day • Titration frequency: week(s) to months • Alternate formulations: “XR” and combinations

  10. Cochrane ReviewJuly 2005 “Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.”

  11. Metformin Outperformed Other Meds in Obese Patients (UKPDS) Lancet 1998 Sep 12;352(9131):854-65.

  12. Insulin Secretagogues: Sulfonylureas (SFU) and “Glinides” Mechanism of action • Stimulate basal and postprandial insulin secretion • Require functioning beta cells (no effect on beta cell dysfunction) • Work quickly Safety and efficacy • Decrease A1Capproximately1-2% • Lower fasting glucose 20% • Adverse events: weight gain, allergy (rare); main risk, hypoglycemia Dosing • Initial dose: 1/8 to 1/4 maximum dose; dosing: 1-2 times/day (SFU), 3 times/day (glinides) • Maximum effective dose: 1/2 maximum(full dose with nateglinide) • Titration frequency: day(s) to weeks

  13. Preferred Sulfonylureas • All available as generic agents Glipizide ER 5-20 mg once per day • Once daily, flat profile, low plasma levels resulting in a low risk of weight gain and hypoglycemia Glipizide 2.5 to 20 mg twice a day • Twice daily. Half-life 2-4 hours, peaks in 2-3 hours. By taking it once a day at low dose it stimulates insulin secretion for 6-12 hours Glimepiride 1-8 mg per day • Once daily. Half-life 9 hours, peak action for 4 hours. Special utility like with glipizide but with longer half-life Buse J. Personal Opinion Melander A. Diabetes 2004;53 Suppl 3:S151

  14. Thiazolidinediones (TZD’s or Glitazones): Pioglitazone and Rosiglitazone Mechanism of action • Enhance insulin sensitivity in muscle, adipose tissue • Inhibit hepatic gluconeogenesis • Reduced rate of beta cell dysfunction Safety and efficacy • Decrease A1C1-2% • Adverse events: edema, weight gain, anemia; rare serious risk: liver failure Dosing • Initial dose (monotherapy): 1/2 to 2/3 maximum; dosing,1-2 x/day • Maximum effective dose: maximum dose • Titration frequency: weeks to month(s)

  15. TZDs: Weight Gain and Edema • Derived from an increase in body fat and possibly increased fluid retention • Severity appears to be proportional to level of glycemic control achieved • Not inevitable and diet helps • Accentuated by combination with secretagogues or insulin • Usually mild to moderate and well tolerated Patients should be instructed to inform their doctors of rapid or excessive weight gain Lebovitz H. Diabetes Metab Rev 2002;18:S23 Fonseca V. Am J of Med 2003;115:42S

  16. Oral Hypoglycemics TZD Lipid Effects • Rosiglitazone(Avandia) • +LDL • +HDL • +Triglycerides • Pioglitazone (Actos) • +LDL • +HDL • -Triglycerides • Rosiglitazone – Black box warning for CHF and ischemic heart disease; warnings about increased fracture risk in women • Pioglitzaone – Black box warning for CHF and warning about increase fracture risk. No evidence to suggest increased ischemic heart disease.

  17. TZD Lipid EffectsRCT = 735 patients1 1. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005 Jul;28(7):1547-54.

  18. AHA/ADA Consensus Statement for TZDs • Not recommended for patients with NY Heart Association class III or IV heart failure • TZDs alone, or particularly in combination with insulin, may cause fluid retention which can lead to heart failure • Incidence of CHF <1% with TZD monotherapy • Increased to 2%-3% in combination with insulin • Patients should be observed for signs and symptoms of heart failure • TZDs should be discontinued if any deterioration in cardiac status occurs Nesto RW et al. Diabetes Care 2004;27:256

  19. Alpha-Glucosidase Inhibitors: Acarbose And Miglitol Mechanism of action • Delay absorption of carbohydrates • Depend upon postprandial hyperglycemia Safety and efficacy • Decrease A1C0.5-1% • Adverse events: flatulence; main risk: rare liver enzyme elevation Dosing • Initial dose: 1/4 maximum once daily; dosing: 3 times daily • Maximum effective dose: 1/2 maximum dose • Titration frequency: week(s) to months

  20. INCRETINSRole of Glucagon Like Peptide (GLP-1) in Glucose Homeostasis

  21. Incretin Drugs Exenatide (Byetta) – GLP-1 analog • Injection twice daily • 5mcg bid AC x 1 month, then 10mcg bid AC • Beneficial effects described previously • Expensive • Weight loss • Reduction in HgBA1C Sitagliptin (Januvia)– DPP4 inhibitor • Technically not an incretin but similar effects • Oral administration • 100mg daily • Weight neutral

  22. Incretins Play an Important Role in Glucose Homeostasis Food ingestion  Insulin from beta cells (GLP-1 and GIP) Glucose Dependent ↑Glucose uptake by peripheral tissue2,4 Release of gut hormones— Incretins1,2 Pancreas2,3 ↓ Blood glucose Beta cellsAlpha cells GI tract Active GLP-1 & GIP ↓Glucose production by liver  Glucagon fromalpha cells (GLP-1) Glucose Dependent DPP-4 enzyme InactiveGIP InactiveGLP-1 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

  23. Value of Adding Instead of Switching Continue Glyburide SwitchTo Metformin 0.5 AddMetformin 0.0 * -0.5 * * * Mean ChangeFrom Baseline A1C (%) -1.0 -1.5 † -2.0 † † † † † -2.5 0 9 13 17 21 29 n=632 *P<0.01 †P<0.001 25 Week DeFronzo RA et al. NEJM 1995;333:541

  24. Key Points to Consider for Therapy Maximal benefits of metformin are observed at the recommended daily dose of 2000 mg (1 g BID)1 Thiazolidinediones should be started at low doses and slowly increased to minimize side effects2 Glucose-lowering effects of a sulfonylurea plateau at half the maximum recommended dose3 Garber AJ et al. Am J Med 1997;103:491 Nesto RW et al. Diabetes Care 2004;27:256 Stenman S et al. Ann Intern Med 1993;118:169

  25. Current Treatment ParadigmPathophysiology-Oriented Approach Intensify Combinations Of Oral Agents Monotherapy vs Early Combinations Of Oral Agents Lifestyle Changes • Combination therapy from the outset • Treatment designed to address the underlying pathophysiology • Vigorous effort to meet glycemic targets • Simultaneous rather than sequential therapy • Early stepwise titrations to meet glycemic targets Add Insulin Harris MI et al. Diabetes Care 1999;22:403 Harris MI et al. Diabetes Care 1998;21:518

  26. At a routine health maintenance visit, a 42-year-old obese male is found to have a fasting plasma glucose level of 118 mg/dL. Which one of the following is the most appropriate initial intervention for preventing or delaying the development of diabetes in this patient?A) Lifestyle modificationB) Metformin (Glucophage)C) A thiazolidinedioneD) An oral sulfonylurea agentE) An ACE inhibitor

  27. Mark all options below that are true regarding the use of thiazolidinediones (TZDs).A) The full hypoglycemic effect is seen 2 weeks after the initiation of a given doseB) The hypoglycemic effect is comparable to that of metformin (Glucophage) or a sulfonylureaC) Monitoring of liver enzymes is recommendedD) Weight gain and edema are commonly associated with their useE) Their mechanism of action is enhancement of insulin sensitivity

  28. A 62-year-old female is diagnosed with type 2 diabetes on the basis of consecutive fasting plasma glucose levels of 138 mg/dL and 143 mg/dL. Which of the following should be prescribed as part of her initial management? (Mark all that are true.)A) Lifestyle interventionB) Metformin (Metformin)C) An oral sulfonyureaD) A thiazolidinedioneE) Pramlintide

  29. Hypoglycemia is a possible side effect of which of the following diabetes agents? (Mark all that are true.)A) InsulinB) Pioglitazone (Actos)C) Metformin (Glucophage)D) SulfonylureasE) Repaglinide (Prandin)F) Acarbose (Precose)

  30. A 29-year-old female with polycystic ovary syndrome asks if you can correct her oligomenorrhea and infertility. Her fasting glucose level is 100 mg/dL and she has a normal glycosylated hemoglobin level. Which of the following diabetes medications have been found to address these problems? (Mark all that are true.)A) Glyburide (Micronase, DiaBeta)B) Metformin (Glucophage)C) Pioglitazone (Actos)D) Miglitol (Glyset)E) Repaglinide (Prandin)

  31. Mark all options below that are true regarding the use of metformin (Glucophage).A) Its efficacy as a hypoglycemic agent is comparable to that of sulfonylureasB) It has a lower secondary failure rate than sulfonylureasC) Its hypoglycemic effect is additive to the action of sulfonylureasD) Gastrointestinal side effects cause 20%-30% of patients to discontinue its useE) It is contraindicated in patients with a serum creatinine exceeding 1.5 mg/dL for males or 1.4 mg/dL for females

  32. Which of the following oral agents should be used with caution in patients with advanced heart failure? (Mark all that are true.)A) ThiazolidinedionesB) Metformin (Glucophage)C) SulfonylureasD) MeglitinidesE) Alpha-glucosidase inhibitors

  33. At a routine health maintenance visit, a 42-year-old obese male is found to have a fasting plasma glucose level of 118 mg/dL. Which one of the following is the most appropriate initial intervention for preventing or delaying the development of diabetes in this patient?A) Lifestyle modificationB) Metformin (Glucophage)C) A thiazolidinedioneD) An oral sulfonylurea agentE) An ACE inhibitor

  34. Hypoglycemia is a possible side effect of which of the following diabetes agents? (Mark all that are true.)A) InsulinB) Pioglitazone (Actos)C) Metformin (Glucophage)D) SulfonylureasE) Repaglinide (Prandin)F) Acarbose (Precose)

  35. Which one of the following oral agents is most likely to produce weight loss in the diabetic patient?A) ThiazolidinedionesB) Metformin (Glucophage)C) SulfonylureasD) MeglitinidesE) Alpha-glucosidase inhibitors

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