Nathalie M. Merle                            PharmD Student                        University of Florida                  ...
Overview   Heart Failure   Insulin Resistance   Thiazolidinediones   Case Reports   Alternative Therapy   Conclusion
Heart Failure“A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs ...
Epidemiology2  5 million Americans in 1996  10 million expected in 2007  400,000 – 700,000 new diagnosis / year  Nearl...
Etiology2      Systolic Dysfunction         Diastolic Dysfunction   Muscle Mass                Ventricular Hypertrophy...
Pathophysiology                CO = HR x SVCompensatory mechanisms to maintain CO     Tachycardia  & Contractility     F...
Clinical PresentationRV Dysfunction     LV Dysfunction    NonspecificPeripheral Edema   Pulmonary Edema   Exercise Intoler...
NYHA Functional Classification  Class I      No limitations of physical activity  Class II      Slight limitations of ...
Precipitating and Exacerbating Factors                 of HF2  Noncompliance                            Drugs  Inadequat...
High Risk Groups2  Systemic Hypertension  Coronary Artery Disease  Diabetes Mellitus  History of cardiotoxic drugs  R...
Metabolic Abnormalities: Diabetes            Circulation. 2003;108:1527
Thiazolidinediones (TZD)3Avandia® Rosiglitazone, Actos® Pioglitazone  Mode of Action     Peroxisome    proliferator-acti...
Metabolic Abnormalities: Diabetes                                                                   Circulation. 2003;...
TZD: Potential Advantages4   peripheral vascular resistance   blood pressure  Improve cardiac metabolism  Coronary v...
TZD: Potential Disadvantages4  Fluid Retention*  Peripheral edema   Body Weight (*)  Transient  Hematocrit   Plasm...
Theoretical Mechanisms:TZD – Edema5  Plasma Volume Expansion   Sodium Renal Excretion  Suppression of Endothelin   V...
Actos® Pioglitazone6 & Avandia® Rosiglitazone7Warnings  Fluid retention; may exacerbate or lead to HF.  Combination with...
Preexisting Medical Conditions6,7     Avandia: 26 Wk-Study                Actos: 16 Wk-Study  216 pts Avandia 4mg / Insul...
Edema, Weight Gain, and Anemia6,7     Avandia: 26 Wk-Study            Actos: 16 Wk-Study  Significant  Volplasma     We...
Thiazolidinediones-Associated Congestive Heart Failure and     Pulmonary Edema     Mayo Clinic Proceedings 2003;78:1088-1091
Patients and Methods  648 patients treated with TZD     28%  Actos® pioglitazone      72% Avandia® rosiglitazone  Retr...
Clinical Characteristics          No Preexisting CHF                NYHA II CHF  66-78 years of age                   67...
Results and Discussion  No acute cardiac event explaining deterioration     Renal   Insufficiency: 4 cases      Ischemi...
ACC/AHA Guidelines1    “Diabetics with HF have worse prognosis”“It is prudent to manage,…, DM in patients with HF         ...
Alternative Anti-Diabetic Agents3          Drug               FBG         HbA1c                            (mg/dL)   ( b...
Recommendations for MGMT  ALERT: Dose Titration     3  months after TZD initiation (HbA1c response)  ALERT: MDD      A...
Conclusion  1/3 of HF patients have DM1     6 million Diabetics: Actos® or Avandia®  HF and Insulin Resistance      TZ...
Recommended Readings  Wang CH, Weisel RD, Liu PP, Fedak PWM, Verma SV. Glitazones  and Heart Failure: Critical Appraisal f...
References1    American College of Cardiology [resource on World Wide Web]. URL:     http://www.acc.org. ACC/AHA Guideline...
References7     Avandia® prescribing information. Research Triangle Park, NC:      GlaxoSmithKline; 2003 March8     Kerman...
References14    Nichols GA, Hiller TA, Erbey JR, Brown JB. Congestive Heart Failure in      Type 2 Diabetes: Prevalence, I...
Management of Fluid Status1Goal     Stable     EuvolemiaStatus of Renal Perfusion     Low  doses of loop diuretics / di...
Insulin Edema  Rare complication  Frequently seen earlier years of insulin therapy  Mostly seen when dysregulated patie...
Sulfonylureas  Glimepiride, Glipizide, Glyburide  Mode of Action      1o:  insulin secretion by // K+ channel      2o...
Meglitinides  Prandin® Repaglinide, Starlix® Nateglinide  Mode of Action      1o:  BG by  releases insulin in respons...
α-Glucosidase Inhibitors  Precose® Acarbose, Glyset® Miglitol  Mode of Action      Inhibits enzyme in SI to slow digest...
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Exacerbation of Heart Failure : Thiazolidinediones

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Exacerbation of Heart Failure : Thiazolidinediones

  1. 1. Nathalie M. Merle PharmD Student University of Florida September 24, 2003Exacerbation of Heart Failure:Thiazolidinediones
  2. 2. Overview   Heart Failure   Insulin Resistance   Thiazolidinediones   Case Reports   Alternative Therapy   Conclusion
  3. 3. Heart Failure“A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”1
  4. 4. Epidemiology2  5 million Americans in 1996  10 million expected in 2007  400,000 – 700,000 new diagnosis / year  Nearly 300,000 deaths / year  In 1991 > 2 million hospitalizations  HF management = $56 billion in 1996
  5. 5. Etiology2 Systolic Dysfunction Diastolic Dysfunction   Muscle Mass   Ventricular Hypertrophy  Dilated Cardiomyopathies   Myocardial Ischemia and  Ventricular Hypertrophy Infarction   Valve Stenosis   Pericardial Disease
  6. 6. Pathophysiology CO = HR x SVCompensatory mechanisms to maintain CO   Tachycardia & Contractility   Frank-Starling Mechanism   Vasoconstriction   Ventricular Hypertrophy & Remodeling
  7. 7. Clinical PresentationRV Dysfunction LV Dysfunction NonspecificPeripheral Edema Pulmonary Edema Exercise IntoleranceJVD Dyspnea FatigueHepatomegaly Tachypnea NocturiaAscites Hemoptysis Tachycardia
  8. 8. NYHA Functional Classification  Class I   No limitations of physical activity  Class II   Slight limitations of physical activity  Class III   Marked limitation of physical activity  Class IV   Symptoms present at rest / exacerbated upon physical activity
  9. 9. Precipitating and Exacerbating Factors of HF2  Noncompliance Drugs  Inadequate therapy   Cardiotoxicity  Cardiac ischemia   Negative Inotropic Effects  Cardiac arrhythmias   Na+ and H2O Retention  Uncontrolled hypertension   Thiazolidinediones:  Volume
  10. 10. High Risk Groups2  Systemic Hypertension  Coronary Artery Disease  Diabetes Mellitus  History of cardiotoxic drugs  Rheumatic fever  Family history of cardiomyopathy
  11. 11. Metabolic Abnormalities: Diabetes Circulation. 2003;108:1527
  12. 12. Thiazolidinediones (TZD)3Avandia® Rosiglitazone, Actos® Pioglitazone  Mode of Action   Peroxisome proliferator-activated receptor agonists (PPAR)    insulin sensitivity and  hepatic glucose production
  13. 13. Metabolic Abnormalities: Diabetes     Circulation. 2003;108:1527
  14. 14. TZD: Potential Advantages4   peripheral vascular resistance   blood pressure  Improve cardiac metabolism  Coronary vasodilation   Endothelin-1 level  Improve endothelial function
  15. 15. TZD: Potential Disadvantages4  Fluid Retention*  Peripheral edema   Body Weight (*)  Transient  Hematocrit   Plasma Volume  Contraindicated: NYHA III/IV and liver disease
  16. 16. Theoretical Mechanisms:TZD – Edema5  Plasma Volume Expansion   Sodium Renal Excretion  Suppression of Endothelin   Vascular Permeability
  17. 17. Actos® Pioglitazone6 & Avandia® Rosiglitazone7Warnings  Fluid retention; may exacerbate or lead to HF.  Combination with insulin may  risk of CV adverse events.  Discontinue if deterioration in cardiac status.  NYHA Class III/IV not studied during clinical trials. Not Recommended.Renal Impairment  No dosage adjustment.
  18. 18. Preexisting Medical Conditions6,7 Avandia: 26 Wk-Study Actos: 16 Wk-Study  216 pts Avandia 4mg / Insulin   191 on Actos 15mg / Insulin  322 pts Avandia 8mg / Insulin   188 on Actos 30mg / Insulin  388 pts Insulin   187 on Insulin  Distribution of preexisting   Distribution: 2.3% CHF (13 medical conditions not pts) disclosed   4 pts  CHF (0.01%)   edema and HF with combo   History of CVD
  19. 19. Edema, Weight Gain, and Anemia6,7 Avandia: 26 Wk-Study Actos: 16 Wk-Study  Significant  Volplasma   Weight Gain:  Weight Gain:   Δ 1.0 Kg on 30 mg   Δ 3.1 Kg on 8 mg   Δ 0.9 Kg on 15 mg   Δ 1.0 Kg on 4 mg   Hematology: 4 -12 weeks  Hematology: 3 months    2-4% Hgb   1.0 gm/dL Hgb    3.3% Hct
  20. 20. Thiazolidinediones-Associated Congestive Heart Failure and Pulmonary Edema Mayo Clinic Proceedings 2003;78:1088-1091
  21. 21. Patients and Methods  648 patients treated with TZD   28% Actos® pioglitazone   72% Avandia® rosiglitazone  Retrospective chart review   6 male NYHA I-II patients   New onset CHF and pulmonary edema (PE)  Recent TZD initiation   Duration 1-16 months   Dose  3 weeks to 3 months  TZD discontinued / diuretics administered
  22. 22. Clinical Characteristics No Preexisting CHF NYHA II CHF  66-78 years of age   67 years old  Diabetes: 4-21 years   Diabetes: 20 years  All 5 on Rosiglitazone   Pioglitazone  Max Dose (8 mg): 4 out of 5   Max Dose (45 mg)  TZD duration: 1, 6, 8,16 months   TZD duration: 7 months  Weight gain (Kg): 1, 5, 6, 9, 12   Weight gain: 8 kg  Insulin, glyburide, glipizide   Insulin  3 Hospitalization   Hospitalization
  23. 23. Results and Discussion  No acute cardiac event explaining deterioration   Renal Insufficiency: 4 cases   Ischemic Cardiomyopathy: 1 case  Signs/symptoms resolved in all 6 with d/c of TZD  6 cases ~ 0.9% of TZD-treated population  Authors conclude   NYHA I or II ~ risk for TZD-associated HF   Canadian Adverse Reaction Monitoring Program: 9 reports HF and PE due to TZD6,7
  24. 24. ACC/AHA Guidelines1 “Diabetics with HF have worse prognosis”“It is prudent to manage,…, DM in patients with HF as if the patients did not have HF”“Thiazolidinediones should be used with caution in such patients”
  25. 25. Alternative Anti-Diabetic Agents3 Drug FBG HbA1c (mg/dL) ( baseline)Sulfonylureas 40-60 1-2%Repaglinide / Nateglinide 30.3 1.1%α-Glucosidase Inhibitors 20-30 0.3-0.9%TZD 20-55 0.1-0.9
  26. 26. Recommendations for MGMT  ALERT: Dose Titration   3 months after TZD initiation (HbA1c response)  ALERT: MDD   Avandia (8mg); Actos (45mg)  Cardiologist - Endocrinologist Communication  Edema and Weight Gain   TZD dose adjustment   Switch to a TZD associated with less weight gain   Caution against TZD - insulin combination4,5,7   Diuretic Resistance  d/c TZD  Educate patient on early recognition of fluid overload
  27. 27. Conclusion  1/3 of HF patients have DM1   6 million Diabetics: Actos® or Avandia®  HF and Insulin Resistance   TZD enhance insulin sensitivity  Case Reports6: TZD  HF   Max Dose: 5 out of 6 patients   Dose Increase: 3 weeks to 3 months  Establish mechanism of action for fluid retention  Long term clinical trials
  28. 28. Recommended Readings Wang CH, Weisel RD, Liu PP, Fedak PWM, Verma SV. Glitazones and Heart Failure: Critical Appraisal for the Clinician. Circulation 2003; 107; 1350-1354 Swan JW, Anker ST, Walton C, Godsland IF, et al. Insulin Resistance in Chronic Heart Failure: Relation to Severity and Etiology of Heart Failure.
  29. 29. References1  American College of Cardiology [resource on World Wide Web]. URL: http://www.acc.org. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. Available from the internet. Accessed 2003, Sept 10.2  Johnson JA, Parker RB, Patterson JH. Heart Failure. In Pharmacotherapy: A Pathophysiologic Approach. 5th ed. Dipiro JT, Talbert RL, Yee GC et al., eds. New York: McGraw-Hill; 2002;185-2183  AACE Medical Guidelines for the Management of Diabetes Mellitus: The AACE System of Intensive Diabetes Self-Management. Endocrine Practice 2002;8;40-654  Wang CH, Weisel RD, Liu PP, Fedak PWM, Verma SV. Glitazones and Heart Failure: Critical Appraisal for the Clinician. Circulation 2003; 107; 1350-13545  Wilson Tang WH, Francis GS, Hoogwerf BJ, Young JB. Fluid Retention After Initiation of Thiazolidinediones Therapy in Diabetic Patients with Established Chronic Heart Failure. JACC 2003; 41(8); 1394-13986  Actos® prescribing information. Lincolnshire, IL: Takeda Pharmaceuticals North America, Inc; 2002 July
  30. 30. References7  Avandia® prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2003 March8  Kermani A, Garg A. Thiazolidinedione-Associated Congestive Heart Failure and Pulmonary Edema. Mayo Clinic Proceedings 2003;78;1088-10919  Wooltorton E. Rosiglitazone (Avandia) and Pioglitazone (Actos) and heart failure. CMAJ. 2002;166(2)219. Editorial.10  Swan JW, Anker ST, Walton C, Godsland IF, et al. Insulin Resistance in Chronic Heart Failure: Relation to Severity and Etiology of Heart Failure.11  Creager MA, Luscher TF. Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part 1. Circulation 2003; 108: 1527-153212  Oki JC, Isley WL. Diabetes Mellitus. In Pharmacotherapy: A Pathophysiologic Approach. 5th ed. Dipiro JT, Talbert RL, Yee GC et al., eds. New York: McGraw- Hill; 2002;1335-135813  Page II RL, Gonzansky WS, Ruscin JM. Possible Heart Failure Exacerbation Associated with Rosiglitazone: Case Report and Literature Review. Pharmacotherapy 2003; 23(7): 945-954
  31. 31. References14  Nichols GA, Hiller TA, Erbey JR, Brown JB. Congestive Heart Failure in Type 2 Diabetes: Prevalence, Incidence, and Risk Factors. Diabetes Care 2001;24(9);1614-161915  Davis SN, Granner DK. Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Pancreas. In Goodman and Gilman’s the Pharmacological Basis of the Therapeutics. 10th ed. Hardman JG, Limbrid LE, Gilman AG. New York: McGraw-Hill; 2001;1679-171416  Actos®-Congestive Heart Failure. Medical Services Department of Takeda Pharmaceuticals North America. Facsimile received 2003, Sept 18.
  32. 32. Management of Fluid Status1Goal   Stable   EuvolemiaStatus of Renal Perfusion   Low doses of loop diuretics / dietary sodium restriction    loop diuretics add 2nd diuretic (metolazone)   High dose IV diuretics +/- IV dopamine or dobutamine   Ultrafiltration or hemofiltration
  33. 33. Insulin Edema  Rare complication  Frequently seen earlier years of insulin therapy  Mostly seen when dysregulated patients with progressive weight loss are treated with relatively high amounts of insulin  May aggravate pulmonary edema, CHF, HTN  Treatment:  insulin dose; edema subsidizes 3-4 days
  34. 34. Sulfonylureas  Glimepiride, Glipizide, Glyburide  Mode of Action   1o:  insulin secretion by // K+ channel   2o:  hepatic glucose production  Contraindications   Hypersensitivity, DK, sulfa allergy  Adverse Effects   Hypoglycemia, hypersensitivity, weight gain
  35. 35. Meglitinides  Prandin® Repaglinide, Starlix® Nateglinide  Mode of Action   1o:  BG by  releases insulin in response to meals   2o:  FBG and PPBG  Contraindications   Diabetic Ketoacidosis, hypersensitivity  Adverse Effects   Hypoglycemia, weight gain
  36. 36. α-Glucosidase Inhibitors  Precose® Acarbose, Glyset® Miglitol  Mode of Action   Inhibits enzyme in SI to slow digestion of carbohydrates, delay glucose absorption, and reduce  in PPBG  Contraindications   GI disorders, chronic ulceration, malabsorption, or intestinal obstruction  Adverse Effects   Flatulence and abdominal bloating

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