Anemia due to Coadministration of Renin-Angiotensin-System Inhibitors and PPARγ Agonists in Uncomplicated Diabetic Patients

 

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Abstract

Aims:

Therapy with either angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB) or thiazolidinediones (TZD) is associated with dose-dependent decrements in hematocrit and hemoglobin levels. We aimed to investigate the impact of the coadministration of TZD and ACEI/ARB on hematocrit and hemoglobin values in uncomplicated patients with type 2 diabetes mellitus and normal serum creatinine.

Methods:

Data from patients with type 2 diabetes currently followed, were reviewed and patients treated with ACEI/ARB and/or TZD were identified. For the purpose of this study the following 4 groups of 30 stable non-anemic diabetic patients each matched for age, gender, and BMI were formed. Group ACEI/ARB included patients on ACEI/ARB without TZD, group TZD included patients on TZD and antihypertensive agents other than ACEI/ARB, group ACEI/ARB/TZD consisted of patients on combined therapy with ACEI/ARB and TZD and the control group C included patients never exposed to ACEI/ARB or TZD. Clinical and laboratory data were collected prior to initiation of treatment and after 6 months.

Results:

Neither hematocrit nor hemoglobin showed any significant change from baseline at the end of the study in group C. In both group ACEI/ARB and group TZD a small, but statistically significant reduction in hematocrit (~ 1% point) and hemoglobin levels (~ 0.3 g/dl) was seen. A greater statistically and clinically important reduction in hematocrit (~ 3% points) and hemoglobin (~ 1 g/dl) levels was observed in group ACEI/ARB/TZD. Furthermore, incident anemia at the end reached 7% in group TZD and 23% in group ACEI/ARB/TZD.

Conclusions:

Coadministration of RAS inhibitors and PPAR-γ agonists should be considered in the differential diagnosis of hematocrit lowering and anemia in uncomplicated type 2 diabetic patients with normal serum creatinine. Further studies are required to clarify the mechanism(s), the cardiovascular consequences and the cost utility of anemia workup in such patients.

• References

• 1 American Hospital Formulary Service . Drug Information 1988. Bethesda: American Society of Health-System Pharmacists; 1988: 906
  Google Scholar
• 2 Aso Y, Suganuma R, Wakabayashi S et al. Anemia is associated with an elevated serum level of high-molecular-weight adiponectin in patients with type 2 diabetes independently of renal dysfunction. Transl Res 2009; 154: 175-182
  CrossrefPubMedGoogle Scholar
• 3 Bermudez V, Finol F, Parra N et al. PPAR-gamma agonists and their role in type 2 diabetes mellitus management. Am J Ther 2010; 17: 274-283
  CrossrefPubMedGoogle Scholar
• 4 Berria R, Gastaldelli A, Lucidi S et al. Reduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome. Clin Pharmacol Ther 2006; 80: 105-114
  CrossrefPubMedGoogle Scholar
• 5 Berria R, Glass L, Mahankali A et al. Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus. Clin Pharmacol Ther 2007; 82: 275-281
  CrossrefPubMedGoogle Scholar
• 6 Bhatia V, Chaudhuri A, Tomar R et al. Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes. Diabetes Care 2006; 29: 2289-2294
  CrossrefPubMedGoogle Scholar
• 7 El-Achkar TM, Ohmit SE, McCullough PA et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency. The Kidney Early Evaluation Program Kidney International 2005; 67: 1483-1488
  PubMedGoogle Scholar
• 8 Gossmann J, Burkhardt R, Harder S et al. Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway. Kidney Int 2001; 60: 83-86
  CrossrefPubMedGoogle Scholar
• 9 Hirakata H, Onoyama K, Iseki K et al. Worsening of anemia induced by long-term use of captopril in hemodialysis patients. Am J Nephrol 1984; 4: 355-360
  CrossrefPubMedGoogle Scholar
• 10 Hirase N, Yanase T, Mu Y et al. Thiazolidinedione suppresses the expression of erythroid phenotype in erythroleukemia cell line K562. Leuk Res 2000; 24: 393-400
  CrossrefPubMedGoogle Scholar
• 11 Hollenberg NK. Considerations for management of fluid dynamic issues associated with thiazolidinediones. Am J Med 2003; 115: 111
  PubMedGoogle Scholar
• 12 Iodice C, Balletta MM, Minutolo R et al. Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis. Kidney Int 2003; 63: 2214-2221
  CrossrefPubMedGoogle Scholar
• 13 Ishani A, Weinhandl E, Zhao Z et al. Angiotensin converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2005; 45: 391-399
  CrossrefPubMedGoogle Scholar
• 14 Jacobsen P, Andersen S, Jensen BR et al. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003; 14: 992-999
  CrossrefPubMedGoogle Scholar
• 15 Karalliedde J, Buckingham RE. Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. Drug Saf 2007; 30: 741-753
  CrossrefPubMedGoogle Scholar
• 16 Kim MK, Baek KH, Lim DJ et al. Erythropoietin response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure. J Diabetes Complications 2010; 24: 90-95
  CrossrefPubMedGoogle Scholar
• 17 Kuriyama S, Tomonari H, Tokudome G et al. Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy. Hypertens Res 2002; 25: 849-855
  CrossrefPubMedGoogle Scholar
• 18 Laverman GD, Remuzzi G, Ruggenenti P. ACE inhibition versus angiotensin receptor blockade: which is better for renal and cardiovascular protection?. J Am Soc Nephrol 2004; 15: 64-70
  CrossrefPubMedGoogle Scholar
• 19 Mrug M, Stopka T, Julian BA et al. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997; 100: 2310-2314
  CrossrefPubMedGoogle Scholar
• 20 Nesto RW, Bell D, Bonow RO et al. Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108: 2941-2948
  CrossrefPubMedGoogle Scholar
• 21 Neusschwander-Tetri BA, Brunt EM, Wehmeier KP et al. Interim results of a pilot study demonstrationg the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis. J Hepatol 2003; 38: 434-440
  PubMedGoogle Scholar
• 22 Plata R, Cornejo A, Arratia C et al. Angiotensin converting-enzyme inhibition therapy in altitude polycythaemia:a prospective randomised trial. Lancet 2002; 359: 663-666
  CrossrefPubMedGoogle Scholar
• 23 Rothwell C, McGuire EJ, Altrogge DM et al. Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone. J Toxicol Sci 2002; 27: 35-47
  CrossrefPubMedGoogle Scholar
• 24 Scheen AJ. Combined thiazolidinedione-insulin therapy: should we be concerned about safety?. Drug Saf 2004; 27: 841-856
  CrossrefPubMedGoogle Scholar
• 25 Thomas MC. The high prevalence of anemia in diabetes is linked to functional erythropoietin deficiency. Semin Nephrol 2006; 26: 275-282
  CrossrefPubMedGoogle Scholar
• 26 Vlahakos DV, Canzanello VJ, Madaio MP et al. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 1991; 17: 199-205
  PubMedGoogle Scholar
• 27 Vlahakos DV, Marathias KP, Agroyannis B et al. Posttransplant erythrocytosis. Kidney Int 2003; 63: 1187-1194
  CrossrefPubMedGoogle Scholar
• 28 Vlahakos DV, Marathias KP, Kosmas EN. Losartan reduces hematocrit in patients with chronic obstructive pulmonary disease and secondary erythrocytosis. Ann Intern Med 2001; 134: 426-427
  PubMedGoogle Scholar
• 29 Vlahakos DV, Marathias KP, Madias NE. The Role of the Renin-Angiotensin System in the Regulation of Erythropoiesis. Am J Kidney Dis 2010; 56: 558-565
  CrossrefPubMedGoogle Scholar
• 30 Von Eynatten M, Baumann M, Heemann U et al. Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetes. Eur J Clin Invest 2010; 40: 95-102
  CrossrefPubMedGoogle Scholar
• 31 Wolf G, Müller N, Hunger-Battefeld W et al. Hemoglobin concentrations are closely linked to renal function in patients with type 1 or 2 diabetes mellitus. Kidney Blood Press Res 2008; 31: 313-321
  CrossrefPubMedGoogle Scholar