Exacerbation of Heart Failure : Thiazolidinediones
Nathalie M. Merle PharmD Student University of Florida September 24, 2003Exacerbation of Heart Failure:Thiazolidinediones
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 the ability of the ventricle to fill with or eject blood.”1
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
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
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.
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
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
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 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
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
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
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”
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
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
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.
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
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
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.
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
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
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
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