The document discusses exacerbation of heart failure with the use of thiazolidinediones, providing an overview of heart failure, insulin resistance, and the mechanisms of fluid retention associated with thiazolidinediones based on case reports and clinical trial data. It also reviews guidelines for managing patients with diabetes and heart failure, and recommends alternative anti-diabetic agents or cautious use of thiazolidinediones.

1. Nathalie M. Merle
PharmD Student
University of Florida
September 24, 2003
Exacerbation of Heart Failure:
Thiazolidinediones

2. Overview
 Heart Failure
 Insulin Resistance
 Thiazolidinediones
 Case Reports
 Alternative Therapy
 Conclusion

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. 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. Etiology2
Systolic Dysfunction Diastolic Dysfunction
  Muscle Mass  Ventricular Hypertrophy
 Dilated Cardiomyopathies  Myocardial Ischemia and
 Ventricular Hypertrophy Infarction
 Valve Stenosis
 Pericardial Disease

6. Pathophysiology
CO = HR x SV
Compensatory mechanisms to maintain CO
 Tachycardia & Contractility
 Frank-Starling Mechanism
 Vasoconstriction
 Ventricular Hypertrophy & Remodeling

7. Clinical Presentation
RV Dysfunction LV Dysfunction Nonspecific
Peripheral Edema Pulmonary Edema Exercise Intolerance
JVD Dyspnea Fatigue
Hepatomegaly Tachypnea Nocturia
Ascites Hemoptysis Tachycardia

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. 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. High Risk Groups2
 Systemic Hypertension
 Coronary Artery Disease
 Diabetes Mellitus
 History of cardiotoxic drugs
 Rheumatic fever
 Family history of cardiomyopathy

11. Metabolic Abnormalities: Diabetes
Circulation. 2003;108:1527

12. Thiazolidinediones (TZD)3
Avandia® Rosiglitazone, Actos® Pioglitazone
 Mode of Action
 Peroxisome proliferator-activated receptor agonists
(PPAR)
  insulin sensitivity and  hepatic glucose production

13. Metabolic Abnormalities: Diabetes
 
  Circulation. 2003;108:1527

14. TZD: Potential Advantages4
  peripheral vascular resistance
  blood pressure
 Improve cardiac metabolism
 Coronary vasodilation
  Endothelin-1 level
 Improve endothelial function

15. TZD: Potential Disadvantages4
 Fluid Retention*
 Peripheral edema
  Body Weight (*)
 Transient  Hematocrit
  Plasma Volume
 Contraindicated: NYHA III/IV and liver disease

16. Theoretical Mechanisms:
TZD – Edema5
 Plasma Volume Expansion
  Sodium Renal Excretion
 Suppression of Endothelin
  Vascular Permeability

17. Actos® Pioglitazone6
& Avandia® Rosiglitazone7
Warnings
 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. 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. 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. Thiazolidinediones-Associated
Congestive Heart Failure and
Pulmonary Edema
Mayo Clinic Proceedings 2003;78:1088-1091

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. 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. 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. 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. 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. 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. 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. 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. References
1 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;185-218
3 AACE Medical Guidelines for the Management of Diabetes Mellitus: The
AACE System of Intensive Diabetes Self-Management. Endocrine Practice
2002;8;40-65
4 Wang CH, Weisel RD, Liu PP, Fedak PWM, Verma SV. Glitazones and
Heart Failure: Critical Appraisal for the Clinician. Circulation 2003; 107;
1350-1354
5 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); 1394-1398
6 Actos® prescribing information. Lincolnshire, IL: Takeda Pharmaceuticals
North America, Inc; 2002 July

30. References
7 Avandia® prescribing information. Research Triangle Park, NC:
GlaxoSmithKline; 2003 March
8 Kermani A, Garg A. Thiazolidinedione-Associated Congestive Heart Failure and
Pulmonary Edema. Mayo Clinic Proceedings 2003;78;1088-1091
9 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:
1527-1532
12 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;1335-1358
13 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. References
14 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);1614-1619
15 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;1679-1714
16 Actos®-Congestive Heart Failure. Medical Services Department of Takeda
Pharmaceuticals North America. Facsimile received 2003, Sept 18.

32. Management of Fluid Status1
Goal
 Stable
 Euvolemia
Status 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. 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. 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. 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. 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