Anemia in Diabetes Mellitus

DR. A. P. Naveen Kumar

Chief SpecialistVisakha Steel General Hospital

CASE 1• 52 male HTN , T2DM• Pallor + , edema + , HR -106 , BP - 200/110• Lungs – Bil. Crepts. , CVS – JVP inc. LVS3• Hb. - 6.8 ,FBS -200 , PPBS – 288 • Urea - 124 , Crea. 5.6

CASE -2• 44 F ,HTN, T2DM , CAD - Post PTCA• Vitals normal• Hemodynamically stable• No e/o any retinopathy /neuropathy• On B Blocker , ACE ,Nitrates ,Anti-platelets , Statin• Hb. -9.6 , FBS 104 , PPBS - 166 , Crea. – 0.9 ,Lipids – 154/144/34/94

CASE 3• 44 M T2DM HTN CAD• Asymptomatic• Routine tests show Hb. 11.6 • FBS 112 PPBS 164 Crea. 1.0 Lipids 168/ 136/ 36 / 104• On OHA , ACE , statin , ecosprin

Anaemia is associated with an increased risk of the vascular complications of diabetes including nephropathy, retinopathy, neuropathy, impaired wound healing and macrovascular disease.

There is considerable evidence that anemia exacerbates severity and impairs outcome of peripheral small vessel disease in diabetic patients

• The Third National Health and Nutrition Examination Survey (NHANES-III) reported that patients with diabetes were twice as likely to have anaemia compared to those with similar degree of renal impairment from other causes.

• Nevertheless, there is an increasing number of diabetic patients without renal impairment who are anaemic.

• The pathogenesis of anaemia in these patients is unclear.

Various hypotheses have been proposed• tubulointerstitial disease• chronic renal hypoxia• hyperglycaemia• systemic inflammation• symptomatic autonomic neuropathy causing efferent denervation of the

kidney • loss of appropriate erythropoietin (Epo) production• altered iron metabolism• inhibition of Epo release • drugs

Pathophysiology of Anemia in Diabetic Patients

• EPO release by renal cells has been shown to be modulated by kidney splanchnic innervation. Indeed, renal denervation in animal models led to a loss of EPO production in response to hypoxic stimuli [14, 15]. Furthermore, EPO deficiency has recently been observed in anemic type 1 diabetic patients with severe symptomatic diabetic autonomic neuropathy

• In Bosmans’ study [3], involving a small cohort of patients, the serum EPO levels in anemic diabetic patients were found to be inappropriately low compared to the values observed in a control group of iron deficiency anemic subjects

• A reduced number of specific erythropoietin synthesizing interstitial cells and impairment of the regular processes enabling oxygen sensing through hypoxia-inducible transcription factor-1α (HIF-1α) secondary to interstitial fibrosis or vascular lesions are the main factors involved in anemia in diabetes.

• Other mechanisms may involve cytokine-induced EPO synthesis inhibition [20], hyporeninemia [21], urinary loss of EPO (in patients with nephritic range proteinuria) [22]glycation of the EPO receptor by or secondary to hyperglycemia.

Anaemia in Type 2 Diabetes Mellitus (T2DM) Patients in Hospital Putrajaya

• To date, there is limited data to determine the occurrence of anaemia in diabetics, particularly in a South-East Asian population. Thus, this research aimed to determine the prevalence of anaemia in type 2 diabetes mellitus (T2DM) and its association with sociodemographic, clinical and selected laboratory parameters in a multiethnic Malaysian population in Hospital Putrajaya, a tertiary endocrine centre.

• 165 T2DM patients ≥18 years of age, who visited the endocrine clinic of Hospital Putrajaya from January 2011 to December 2013

CONCLUSIONS• Anaemia is already present in T2DM patients in Hospital Putrajaya at initial

presentation• Regular, early monitoring of Hb level of T2DM should begin at the primary care

setting. • Management of DM at tertiary level should include mandatory routine

haematological tests at follow-up visits enabling aggressive correction of anaemia to prevent other diabetic complications.

• Institution of early reno-protective measures, providing timely intervention in the high-risk group.

• Early identification and correction of anaemia will benefit these patients• However, to what extent and which treatment is the most ideal in terms of balancing

the potential benefits against the adverse risks of treatment is not known.

Treatment of anaemia is one of the ten recommendations for managing patients with CKD in recently published guidelines[25] Others include

• control of blood pressure • protein restriction • management of calcium and phosphate metabolism• blockage of the renin-angiotensin system• control of serum bicarbonate levels• management of cardiovascular risk factors• vascular preservation• immunisation and counselling

Anemia in Patients with Type 2 Diabetes MellitusJéssica Barbieri, 1 Paula Caitano Fontela, 2 Eliane Roseli Winkelmann, 3 , 4 Carine Eloise Prestes Zimmermann, 5 , 6 , *

Yana Picinin Sandri, 4 , 6 Emanelle Kerber Viera Mallet, 6 and Matias Nunes Frizzo 3 , 6

Conclusions• Patients with DM2 and anemia were those with high body mass,

hypertension, increased waist circumference, and longer time of the disease.

• This set of changes characterizes the anemia as chronic disease, which has a significant adverse effect on quality of life of diabetic patients and is associated with the progression of the disease

Relationship between Anemia and Chronic Complications in Chinese Patients with Type 2 Diabetes Mellitus.He BB1, Xu M2, Wei L2, Gu YJ2, Han JF2, Liu YX2, Bao YQ2, Jia WP2.

AIMS:To evaluate the potential association of anemia with micro- and macrovascular complications in Chinese patient with type 2 diabetes mellitus(T2DM).

METHODS: A total of 1997 patients with T2DM were included in this cross-sectional study. Patients were defined as anemic, if hemoglobin (Hb) levels were < 13 g/dL in males and < 12 g/dL in females. Data on demographics, anthropometric parameters, and co-morbidities were extracted for each patient.

CONCLUSIONS: These findings suggest that anemia was related to both micro- and macrovascular complications in Chinese patients with T2DM, but was only an independent risk factor of microvascular complications.

The Study of Hematological Profile of Anemia in Type 2 Diabetes Mellitus Patients with Normal Renal FunctionSwarnkarPranay1, KumarNarender2, VermaKamya3, KumarPankaj1

• Results : During the period of study, a total of 200 patients with type 2 diabetes, male represent 90(45%) and female represent 110 (55%). Forty percent (40%) had anemia. prevalence of anemia was higher in men than in women (25% vs. 15%). blood film of 56 anemic patients shows that 70% with normochromic normocytic anemia, and 20 anemic patient 25% with hypochromic microcytic anemia, and 4 anemic patient 5% shows macrocytic hypochromic anemia.

• Conclusion : Anemia was relatively high prevalence in patients attending routine outpatient, and it's more common in males than females. Routine screening for anemia in the diabetes outpatient clinic, including those without renal impairment is vital

Influence of Iron Deficiency Anemia on Hemoglobin A1C Levels in Diabetic Individuals with Controlled Plasma Glucose LevelsAlap L. Christy, Poornima A. Manjrekar,* Ruby P. Babu, Anupama Hegde, and Rukmini M.S.Dept. of Biochemistry, Centre for Basic Sciences, Kasturba Medical College, Manipal University, Bejai Mangalore

• Iron deficiency anemia elevates HbA1c levels in diabetic individuals with controlled plasma glucose levels. The elevation is more in patients having plasma glucose levels between 100 to 126 mg/dl. Hence, before altering the treatment regimen for diabetes, iron deficiency anemia should be considered

Target Hemoglobin• Currently, there is no recommendation for a different hemoglobin target in diabetic and

non-diabetic patients; a hemoglobin of 11–12 g/dl is thus theoretically appropriate for all patients.

• However, some patients such as those with congestive heart failure, severe symptomatic coronary heart disease or symptomatic cerebrovascular disease may need an appropriate preparations allowing them to reach a hematocrit level higher than usually recommended.

• In the latest ‘Revised European Best Practice Guidelines for the Management of Anemia’ [39], it is even clearly stated that until data become available, it seems reasonable to recommend a cautious approach towards raising hemoglobin concentration to levels >12 g/dl in patients with diabetes, especially with concurrent peripheral vascular disease.

DEFINING ANEMIA

Guideline Definition of Anemia

WHO criteria < 12.5 gm/dlEuropean Best Practice Guidelines (EBPG) 2004 Anemia Guideline

<12.0 g/d: in males and postmenopausal females; <11.0 g/dL in premenopausal females and prepubertal patients

Kidney Disease Outcomes Quality Initiative (KDOQI) Anemia Guideline

<13.5 g/dL males<12 g/dL females

Anemia is usually defined as a decrease in number of red blood cells (RBCs) or the amount of hemoglobin in the blood

 1.Stedman's medical dictionary (28th ed. ed.).

Causes of AnemiaBroadly, causes of anemia may be classified as impaired red blood cell (RBC) production, increased RBC destruction.

Impaired productionDisturbance of proliferation and differentiation of stem cell

1. Pure red cell aplasia2. Aplastic anemia affects all kinds of blood cells. Fanconi anemia is a hereditary disorder or

defect featuring aplastic anemia and various other abnormalities.3. Anemia of renal failure by insufficient erythropoietin production4. Anemia of endocrine disorders

Disturbance of proliferation and maturation of erythroblasts

1. Pernicious anemia is a form of megaloblastic anemia due to vitamin B12 deficiency dependent on impaired absorption of vitamin B12. Lack of dietary B12 causes non-pernicious megaloblastic anemia

2. Anemia of folic acid deficiency as with vitamin B12, causes megaloblastic anemia3. Anemia of prematurity, by diminished erythropoietin response to declining hematocrit levels,

combined with blood loss from laboratory testing, generally occurs in premature infants at two to six weeks of age.

4. Iron deficiency anemia, resulting in deficient heme synthesis5. Thalassemias, causing deficient globin synthesis6. Congenital dyserythropoietic anemias, causing ineffective erythropoiesis7. Anemia of renal failure

Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.

Anemia due to increased RBC destruction• Anemias of increased red blood cell destruction are generally classified as hemolytic anemias.

Intrinsic (intracorpuscular) abnormalities cause premature destruction. All of these, except paroxysmal nocturnal hemoglobinuria, are hereditary genetic disorders.

1. Hereditary spherocytosis is a hereditary defect that results in defects in the RBC cell membrane, causing the erythrocytes to be sequestered and destroyed by the spleen.

2. Hereditary elliptocytosis is another defect in membrane skeleton proteins.3. Abetalipoproteinemia causing defects in membrane lipids4. Enzyme deficiencies5. Hemoglobinopathies

• Sickle cell anemia• Hemoglobinopathies causing unstable hemoglobins

Saunders Elsevier. p. 432 ISBN 978-1-4160-2973-1

CKD ASSOCIATED ANEMIA

A normochromic, normocytic anemia usually accompanies progressive CKD , and the overall prevalence of CKD-associated anemia is approximately 50%.

Although anemia may be diagnosed in patients at any stage of CKD, there is a strong correlation between the prevalence of anemia and the severity of CKD[1]

While anemia in CKD can result from multiple mechanisms (iron, folate, or vitamin B12 deficiency; gastrointestinal bleeding; severe hyperparathyroidism, systemic inflammation, and shortened red blood cell survival), decreased erythropoietin synthesis is the most important and specific etiology causing CKD-associated anemia.

1.Thomas R, Kanso A, Sedor JR. Prim Care. Chronic kidney disease and its complications 2008 Jun;35(2):329-44

Erythropoietin in Anemia of Chronic Kidney Disease

The Role of Erythropoietin in Erythropoiesis

Erythropoietin ensures the maturation of progenitor cells into RBCs

Erythropoietin rescues neocytes from apoptosis

Erythropoietin helps to sustain RBC proliferation and differentiation

Erythropoietin (EPO)

Regulation of ErythropoiesisFeedback loop

Erythropoietin

RBCsErythroid marrow

CirculatingRBCs

Kidney

Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

O2

Erslev & Besarab. Kidney Int. 1997;51:622-630

GM-CSFIL-3, IGF-1SCF

Erythropoietin

Stage 1: CD-34 Stage 2: ErythronStem cell pool

Progenitor cellsBFU-E, CFU-E

Mature cellsPrecursor cellserythroblasts

The Role of Erythropoietin in Erythropoiesis

Hb O2transportcapacity

peripheral hypoxia

kidneyperitubular cells

serum EPO

precursor cells

erythroblasts

reticulocytes erythrocytesHb

O2transportcapacity

Hb and Erythropoietin:the Non-Anaemic Patient

EPO=erythropoietin

Erythropoietin

RBCsErythroid marrow

CirculatingRBCs

Kidney O2

CKD: Regulation of ErythropoiesisDisrupted feedback loop

Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

Adapted from Caro et al. J Lab Clin Med. 1979;93:449-458

Defining Renal Anaemia Erythropoietin levels in patients with non-renal and renal anaemia

Bilateral nephrectomy

Non-renal anaemia

CKD

100 000

10 000

1000

100

10

1

Serum EPO (mU/mL)

0 10 20 30 40 50 60 70Haematocrit, %

Erythropoietin and the Pathophysiology of Renal anaemia

• Renal disease in progressive renal failure is almost always accompanied by a normochromic, normocytic anaemia†

• Severity of anaemia correlates with severity of kidney disease

• Anaemia associated with kidney disease results from multiple factors

• failure of the erythropoietin response as a result of kidney damage• significant reduction in circulating RBC lifespan secondary to uraemia• reduced bone marrow response to circulating erythropoietin

†anaemia characterised by RBCs which are normal in morphology and Hb content, but are too few to sustain adequate oxygen transport

Hb O2transportcapacity

peripheral hypoxia

kidneyperitubular cells

serum EPO

precursor cells

erythroblasts

reticulocytes erythrocytesHb

O2transportcapacity

Hb AND ERYTHROPOIETIN: THE ANAEMIC PATIENT WITH CKD

DAMAGED

INSUFFICIENT

ANAEMIA

Relationship between EPO and Iron• Erythropoiesis involves the close association between iron and erythropoietin.• If erythropoietin is the vehicle that drives erythropoiesis, then iron is the fuel needed for

production of new red blood cells. • In the optimal presence of both, red cell production occurs briskly and efficiently. If one

component is absent (e.g., iron), anemia develops.

Role of erythropoietin and iron in erythropoiesis

CONSEQUENCES OF ANEMIA

Reduced oxygen delivery to tissues

Decrease in Hb compensated by increased cardiac output

Progressive cardiac damage and progressive renal damage1

Increased mortality risk2

Reduced quality of life (QOL)3

• Fatigue• Diminished exercise capacity• Reduced cognitive function

Left ventricular hypertrophy (LVH)4

1. Silverberg et al. Blood Purif. 2003;21:124-130. 2. Collins et al. Semin Nephrol. 2000;20:345-349;

3. The US Recombinant Human Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial. 2003;16:101-105.

Effect of 1g/dL fall in Hb1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0CLVH LV Dil SDF CCF IHD Death

1

1.49 1.55

1.24

1

1.25

Foley et al Am J Kidney Dis 1996; 28: 53-61 .

Rel

ativ

e ris

k

CLVH = concentric left ventricular hypertrophyLV Dil = left ventricular dilatation SDF = systolic dysfunctionCCF = chronic cardiac failureIHD = ischaemic heart disease

Hospitalisation Risk Increases with Hb <11 g/dLDialysis patients

1.16 1.091.00 1.01

1.55

0.0

0.5

1.0

1.5

2.0

<8 8−9.99 10−10.99 11−11.99 ≥12

P=0.77P<0.0001 P=0.001 P=0.05

n=7998

Pisoni et al. Am J Kidney Dis. 2004;44:94-111

RR of hospitalisation

Hb level (g/dL)

Investigations in patient with renal anemiaSince erythropoietin is the commonest but not the only cause of anemia in CKD patients, the initial evaluation should include a variety of tests:

• Complete blood count (CBC) including—Hb concentration and red blood cell indices (mean corpuscular hemoglobin [MCH], mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC]), white blood cell count, differential count and platelet count.

• Absolute reticulocyte count to assess bone marrow responsiveness (if indicated).• Serum ferritin to assess iron stores.• Serum transferrin saturation (TSAT) or reticulocyte Hb content (CHr) to assess adequacy of iron

for erythropoiesis.• Percentage of hypochromic red blood cells (HRC).• Plasma/serum C-reactive protein (CRP) - to assess inflammation.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1-150

Algorithm for anemia work up in patients with CKD 

What do we hope to achieve by the early treatment of renal anaemia?

• Increased exercise capacity, improved quality of life, cognitive function and sexual function

• Regression of left ventricular hypertrophy

• Reduced mortality and hospitalisation

• Reduced transfusion requirements

• ?Regression of chronic renal failure progression

EPO Non responsiveness = >22,000 IU/WK.

Most common cause is iron deficiencyChronic blood loss ( particularly GI )Infection / Inflammation ( measure CRP )Severe Hyper Parathyroidism ( causes bone

marrow fibrosis )Aluminium toxicityHemoglobinopathiesB 12 or Folate deficiency

HemolysisOccult malignancyInadequate DialysisPRCAMalnutritionInadequate dosingPoor compliance

Anemia Management Guidelines

DIAGNOSIS AND EVALUATION OF ANEMIA IN CKD

Guidelines for Frequency of Testing for Anemia

For CKD patients without anemia, measure Hb concentration when clinically indicated:

At least annually in patients with CKD 3At least twice per year in patients with CKD 4–5ND

At least every 3 months in patients with CKD 5HD and CKD 5PD

For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicated:

At least every 3 months in patients with CKD 3–5ND and CKD 5PDAt least monthly in patients with CKD 5HD

Diagnosis and evaluation of anemia in CKD

Guidelines for Investigation of anemia:

• In patients with CKD and anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia:

• Complete blood count (CBC)

• Absolute reticulocyte count

• Serum ferritin level

• Serum transferrin saturation (TSAT)

• Serum vitamin B12 and folate levels

Use of iron to treat anemia in CKD

• GI bleeding

• Multiple blood tests

• HD itself ( upto 2 Gms. of iron per year )

MONITORING IRON STATUS• Target ferritin 150-500 µg /L , avoid > 1000

• Plasma ferritin conc. usually reflects iron status

• It is an acute phase reactant –monitor CRP

• Percentage hypochromic red cells –Target < 10%

• Transferrin saturation (TSAT )> 20% - derived =serum iron /TIBC x 100

• Predialysis give oral iron• Ferritin < 150 start Fe SO4 200mgs TDS ,Fe gluconate 300 mgs TDS

or Ascorbate 100 mgs OD• Oral iron should not be taken with phosphate binder simultaneously• Trial of iron for 4-6 wks. No response change• Dialysis patient give IV iron

Use of iron to treat anemia in CKD

Guidelines: Treatment with Iron Agents

• For adult CKD patients on ESA therapy who are not receiving iron

supplementation, we suggest a trial of IV iron (or in CKD ND

patients alternatively a 1–3 month trial of oral iron therapy) if (2C):

• An increase in Hb concentration or a decrease in ESA dose is desired and

• TSAT is <30% and ferritin is <500 ng/ml (<500 mg/l)

Use of iron to treat anemia in CKDGuidelines: Treatment with Iron Agents

• For CKD ND patients who require iron supplementation, select the route of iron administration based on the

• Severity of iron deficiency

• Availability of venous access

• Response to prior oral iron therapy

• Side effects with prior oral or IV iron therapy

• Patient compliance

• Cost

Use of iron to treat anemia in CKDGuidelines: Iron Status Evaluation

• Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy, including the decision to start or continue iron therapy

• Test iron status (TSAT and ferritin) more frequently when initiating or increasing ESA dose, when there is blood loss, when monitoring response after a course of IV iron, and in other circumstances where iron stores may become depleted

• For patients with absolute iron deficiency (serum ferritin <100 ng/mL and TSAT <20%), the indication for iron therapy should be stronger since the likelihood of obtaining an increase in Hb level following iron therapy is much higher.

Use of ESAs and other agents to treat anemia in CKD

USE OF ESAS TO TREAT ANEMIA IN CKD

Guidelines: ESA Initiation

• Address all correctable causes of anemia (including iron deficiency and inflammatory

states) prior to initiation of ESA therapy

• In initiating and maintaining ESA therapy, we recommend balancing the potential benefits

of reducing blood transfusions and anemia-related symptoms against the risks of harm in

individual patients (e.g., stroke, vascular access loss, hypertension)

• KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease: Volume 2 | Issue 4 | August (2) 2012• Harrison's Principle of Internal Medicine. 18th edition. McGraw Hill Publications

Guidelines: ESA Initiation

For adult CKD ND patients with Hb concentration >10.0g/dl (Z100 g/l),

ESA therapy not be initiated

For adult CKD ND patients with Hb concentration <10.0 g/dl (<100 g/l) the decision whether to initiate ESA therapy be individualized based on

- the rate of fall of Hb concentration, - prior response to iron therapy,- the risk of needing a transfusion, - the risks related to ESA therapy and - the presence of symptoms attributable to anemia

ESA Initiation cont….

• For adult CKD 5D patients, ESA therapy be used to avoid having the Hb

concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the

hemoglobin is between 9.0–10.0 g/dl (90–100 g/l)

• Individualization of therapy is reasonable as some patients may have

improvements in quality of life at higher Hb concentration and ESA therapy may

be started above 10.0 g/dl (100 g/l)

ESA Maintenance Therapy

In general, ESAs not be used to maintain Hb concentration above

11.5 g/dl (115 g/l) in adult patients with CKD. (2C)

Individualization of therapy will be necessary as some patients

may have improvements in quality of life at Hb concentration

above 11.5 g/dl (115 g/l) and will be prepared to accept the risks

In all adult patients, we recommend that ESAs not be used to

intentionally increase the Hb concentration above 13 g/dl (130 g/l)

• We recommend determining the initial ESA dose using the patient’s Hb concentration, body weight, and clinical circumstances

• We recommend that ESA dose adjustments be made based on the patient’s Hb concentration, rate of change in Hb concentration, current ESA dose and clinical circumstances

• We suggest decreasing ESA dose in preference to withholding ESA when a downward adjustment of Hb concentration is needed

ESA DOSING

ESA Administration• For CKD 5HD patients and those on hemofiltration

or hemodiafiltration therapy, we suggest either intravenous or subcutaneous administration of ESA

• For CKD ND and CKD 5PD patients, we suggest subcutaneous administration of ESA

• Frequency of administration• It was suggested that determining the frequency of

ESA administration based on CKD stage, treatment setting, efficacy considerations, patient tolerance and preference, and type of ESA

Numerous ESAs are Currently Available with more

Development

Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130

CERA, continuous erythropoietin receptor activator

Darbepoetin a

t1/2 25–72 hoursEpoetin d

Epoetin at1/2 6–24 hours

Methoxy PEG-epoetin

b (CERA)t1/2 130 hours

Epoetin bt1/2 6–24 hours

2012Hematid

e

1989 2002 20071990

Biosimilarepoetins

HIF-PHI

All ESAs have the same mode of action and maintain Hb in the target range…

Jak2Jak2P P

P P

EPO,rHuEPO EPO dimer EPO mimetic

peptide

Darbepoetinalfa

membrane

C.E.R.A.Peg-rHuEPO

Signal transduction

Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors

Gene activation

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Investigational

Constantinescu SN et al. TEM 1999; Elliott S et al. Nat Biotechnol 2003; Elliott S et al. Exp Hematol 2004; Hasselbeck A et al. Proc ASCO 2003; Tillmann HC et al. Kidney Int 2006; Agoram B et al. NDT 2006; Qui H et al. JBC 1998; Livnah O et al. Science 1996; Wrighton NC et al. Nat Biotechnol 1997

1Agarwal AK, et al. J Intern Med 2006; 2Carrera F, et al. NDT 2006;3Locatelli F, et al. Kidney Int 2001;4Eprex® (Epoetin alfa) SmPC,Janssen-Cilag; 5NeoRecormon® (epoetin beta) SmPC,Roche ;6Aranesp® (darbepoetin alfa) SPC Amgen. 7Mircera® (methoxy polyethylene glycol-epoetin beta) SPC, Roche

Epoetin alfa40

204060

140

Half-

life

(hou

rs)

80100

120

24

Epoetin beta5

13–28

Darbepoetin6

73

PEG-EPO7

139

New carbohydrate side chains

R1 R2

R1

EPO

R2

carbohydrate side chains

Linear Methoxy-Polyethylenglycol (PEG) chain

..but they have a different pharmacokinetic profile

• 5 N-linked (CHO) chains• Maximum 22 sialic acids• MW ~37,100 daltons • 51% carbohydrates

Additional carbohydrate side chains

Receptor 1

Darbepoetin alfa

Receptor 2 Receptor 1

rHuEPO

Receptor 2

Carbohydrate side chains

Darbepoetin alfa has two additional N-linked carbohydrate chains compared with rHuEPO

• 3 N-linked (CHO) chains• Maximum 14 sialic acids • MW ~30,,400 daltons• 40% carbohydrates

Elliott S, et al. Nat Biotechnol. 2003; 414-421.

Darbepoetin alfa has higher serum half-life than epoetins

Unique characters of darbepoetin

Single-dose Pharmacokinetics of IV DA Compared with IV rHuEPO

10

1

0.1

0.01Base

line-

corr

ecte

d D

A se

rum

con

cent

rati

on

(ng/

mL)

0 12 24 36 48 60 72 84 96Time (hours)

Darbepoetin alfa 0.5 µg/kg(n = 11)

rHuEPO 100 U/kg(n = 10)

t1/2 = 25.3 hours

t1/2 = 8.5 hours

Macdougall et al. J Am Soc Nephrol 1999;10:2392

- Darbepoetin alfa is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge

- The greater the sialic acid–containing content of the molecule, the longer its circulating half-life

- Darbepoetin- alpha is 13-14 fold more potent and has 3 fold longer half life compared to rHuEPO

- Half life of darbepoetin alfa(Sc) is 48-72hrs

- 4.3 fold lower epo receptor binding affinity than rHuEPO

Nissenson AR. Am J Kidney Dis. 2001;l38(6): 1390-1397

Unique Characters of Darbepoetin Long term Hb control2Predictable rise in Hb1

Ref: 1. AM J Nephrol 2003;23:106-1112. Therapeutic Apheresis and Dialysis 11 (3): 220-226

Flexible dosing schedule 1

Ref: 1. Nephrol Dial Transplant (2006) 21:2846-2850

Convenient dosing option 2

2. Nissenson AR. Am J Kidney Dis. 2001;l38(6): 1390-1397

Unique Characters of Darbepoetin

Dosage & Administration

• Recommended starting dose for CKD patients on dialysis:

• 0.45 mcg/kg intravenously or subcutaneously weekly

• 0.75 mcg/kg intravenously or subcutaneously every 2 weeks

• Intravenous route is recommended for patients on hemodialysis

• Recommended starting dose for patients with CKD not on

dialysis:

• 0.45 mcg/kg intravenously or subcutaneously at 4 week intervals

Full Prescribing Information of Darbepoetin Alfa. Available on http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103951s5285lbl.pdf

ESA with highest approved dosing interval 1

Ref: 1. NDT Plus (2009) 2 (Suppl 1): i9-i172. Burnkhorst R et al Nephrol Dial Transplant (2004) 19:1224-1230

Unique Characters of Darbepoetin

Darbepoetin offers IV SC Equivalence

Journal Study Outcome

Bommer J et al., NDT (2008) To compare the efficacy of IV and SC Darbepoetin alfa regarding Hb level and doses

Darbepoetin alfa dose requirements were similar (IV and SC both treatment groups)

M.A Baju et al.,Nefro lugia 2009: 29(2); 136-142

Darbepoetin successfully maintain Hb level in patients switched from once weekly to every other week dosing

In patients who were shifted from QW to Q2W the mean Hb level was within the target range

Huggard J et al., Current Medical Research and Opinions 2006:22(10);2023-2430

To determine patient preference for once monthly (QM) Darbepoetin Vs once weekly (QW) or once in 2 weeks (Q2W) Epoetin alfa

Darbepoetin alfa administered once monthly successfully maintained the target Hb % in most Darbepoetin patients.

Suranyl M.G et al., Am J Nephro 2003:106-111

To determine if extending the interval of denovo Darbepoetin alfa adminstration to once other week would be effective and safe in the management of anaemia in CKD

The initiation of Darbepoetin alfa therapy once other week maintain Hb% as targeted by NKF-KDOQ1.

Hajal F et al., Saudi J of Kidney Disease 2009: 20(4); 550-545

To investigate the responses of Darbepoetin Epoetin resistant as well as responsive patient receiving HD

78.6% of the EPO resistant patients responded to darbepoietin raising the Hb level significant for 10-12 gm/dl.

Clinical Evidence for Darbepoetin

Summary- Less frequent dosing .

- Decreased dosing frequency increases compliance and cost effective.

- Darbepoetin is as effective as rHuEPO for maintaining haemoglobin concentration when administered IV or SC.

- Darbepoetin is well tolerated and has a safety profile comparable to that of rHuEPO.

- There have been no reports of antibody formation associated with darbepoetin.

TAKE HOME MESSAGE• Anemia is an important component in T2DM management

• It needs to be periodically monitored

• Correction of anemia improves outcomes in DM

• Overcorrection is not mandated as data shows negative outcomes

THANK

YOU