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Exacerbation of Heart Failure : 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
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
10. High Risk Groups2
Systemic Hypertension
Coronary Artery Disease
Diabetes Mellitus
History of cardiotoxic drugs
Rheumatic fever
Family history of cardiomyopathy
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
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”
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