DIABETES/METABOLISM RESEARCH AND REVIEWS RESEARCH ARTICLE

Diabetes Metab Res Rev 2014; 30: 291–296.

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2491

Diabetes mellitus with normal renal function is

associated with anaemia

Chagai Grossman1,5*† Abstract

Zamir Dovrish2†
Nira Koren-Morag3,5 Background Anaemia is a common complication of diabetes mellitus (DM),
Gil Bornstein4,5 usually related to renal failure. There is scarce information as to the levels of
Avshalom Leibowitz4,5 haemoglobin (Hb) and the rate of anaemia in diabetic patients with normal
renal function. We, therefore, evaluated haemoglobin levels and the rate of
1
Rheumatology Unit, The Chaim anaemia in diabetic subjects with normal renal functions [estimated glomerular
Sheba Medical Center, Tel-Hashomer, filtration rate (eGFR) > 60 mL/min].
Israel
2 Methods The charts of 9250 subjects who attended the Institute of Periodic
Internal Medicine D, Meir Hospital,
Medical Examinations at the Chaim Sheba Medical Center for a routine yearly
Kfar Saba, Israel
3
check-up were reviewed. Four hundred and forty-five subjects with type 2 DM
Department of Epidemiology and and normal renal function were indentified and compared with those without
Preventive Medicine, Tel Aviv
DM who were routinely examined at the same time. Subjects’ electronic
University, Tel Aviv, Israel
records were used to build a biochemical and clinical database.
4
Department of Internal Medicine D,
The Chaim Sheba Medical Center, Results Mean haemoglobin levels were lower in subjects with DM than in those
Tel-Hashomer, Israel without (14.2 vs. 14.7 g/dL, respectively; p < 0.001). Anaemia was observed
5 in 48 (10.8%) subjects in the diabetic group and in only 12 (2.7%) in the
Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel nondiabetic group (p < 0.001). Multivariate analysis revealed that age,
gender, history of gastrointestinal disease, use of beta blockers, renal
*Correspondence to: Chagai function and DM were independent determinants of haemoglobin levels.
Grossman, Rheumatology Unit, The After adjustment for age, gender, history of gastrointestinal tract diseases
Chaim Sheba Medical Center, Tel
and renal function, DM remained a significant determinant of anaemia with
Hashomer, 52621, Israel.
an odds ratio of 2.15 (confidence interval: 1.07–4.31).
E-mail: chagaigr@gmail.com

† Conclusions Anaemia is more common in diabetic patients even when

Chagai Grossman and Zamir Dovrish
eGFR > 60 mL/min. Copyright © 2013 John Wiley & Sons, Ltd.
equally contributed to this work and
are co-first authors of this manuscript.
Keywords diabetes mellitus; renal functions; haemoglobin; anaemia

Received: 9 June 2013
Revised: 22 September 2013
Accepted: 21 October 2013
Introduction
Anaemia is a common complication of diabetes mellitus (DM) and is usually
related to renal failure [1,2]. The rate of anaemia is higher in patients with
diabetic nephropathy than in patients with nondiabetic renal disease with
similar levels of renal function [3–7]. Anaemia is an independent risk factor
for the development and progression of cardiovascular disease and chronic
renal disease and may also contribute to the development and progression of di-
abetic retinopathy and other diabetic complications [8–10]. Several mechanisms

Copyright © 2013 John Wiley & Sons, Ltd.

292
have been suggested explaining anaemia associated with
DM, the most important being erythropoietin deficiency
due to tubulointerstitial renal changes [11].
Several antidiabetic agents such as thiazolidinediones
and biguanides may contribute to the development of
anaemia [12–14]. Moreover, drugs widely used in diabetic
patients that block the renin angiotensin system, such as
angiotensin converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs), may also contribute
to the development of anaemia [15–17]. Most studies
assessing the prevalence of anaemia in diabetic patients
included patients with different levels of renal impair-
ment [3,4,18].
The aim of this study was to assess the haemoglobin
(Hb) levels and rate of anaemia in diabetic patients with
normal renal function. For this purpose, we compared
Hb levels and the rate of anaemia in a group of diabetic
patients with normal renal function with those in a group
of nondiabetic patients. We also studied the effect of
antidiabetic and antihypertensive drugs on Hb levels in
diabetic patients.
Patients and methods
Subjects
During 2010, the charts of 9250 subjects who attended the
Institute of Periodic Medical Examinations at the Chaim
Sheba Medical Center for a routine yearly check-up were
reviewed. Four hundred and forty-five patients were
diagnosed with type 2 DM and normal renal function [esti-
mated glomerular filtration rate (eGFR) > 60 mL/min].
Type 2 DM was diagnosed when fasting plasma glucose
was >126 mg/dL (7.0 mmol/L) on two separate readings,
a history of DM was reported, or when the subject used
insulin or oral hypoglycaemic medications. For each diabetic
subject, a nondiabetic subject with normal renal function
was examined on the same day and at the same time. These
subjects served as controls. Included in the study were
patients with normal renal function [serum creatinine levels
were <1.3 mg/dL (114.9 μmol/L) and eGFR > 60 mL/min].
Patients were excluded if they had a known iron deficiency
or vitamin B12 deficiency anaemia.
Data collection
Data were collected using electronic records. The following
variables were recorded: age, sex, height and weight, blood
pressure levels, fasting glucose levels, HbA1c, serum urea
and creatinine levels, Hb and mean corpuscular volume,
list of medications, data on duration and severity of type
2 DM and comorbidities. We specifically considered the
Copyright © 2013 John Wiley & Sons, Ltd.
C. Grossman et al.
history of gastrointestinal tract disease because these
diseases could be a source of chronic blood loss. A positive
history of gastrointestinal tract disease was defined when a
subject had a history of oesophageal reflux, peptic disease,
diverticulosis or haemorrhoids. eGFR was calculated
according to the Chronic Kidney Disease Epidemiology Col-
laboration equation [19].
Hypercholesterolemia was defined when the measured
fasting total cholesterol was >200 mg/dL (5.3 mmol/L)
or the patient reported using cholesterol lowering medi-
cations. Anaemia was defined when Hb was <12 g/dL
for women and <13 g/dL for men, as established by the
World Health Organization [20].
Statistical analysis
Statistical analyses were performed using statistical
software SPSS version 21.0.
Comparison of groups was determined by independent
t-tests and chi-square tests for continuous and categorical
variables, respectively. To determine which variables were
correlated with Hb levels, Pearson correlations were
calculated for the continuous variables. Adjusting for
confounders significantly correlated in the univariate
analysis, multiple linear regression model and logistic
regression model were constructed for Hb level as contin-
uous variables and anaemia as a dichotomous variable,
respectively. For all analyses, p value of >0.05 was
selected as denoting statistical significance.
Results
Demographic data
The study included 890 subjects (796 men): 445 had type
2 DM and 445 did not. Average duration of DM was
6.1 ± 2.9 years (range 1–30). Subjects with type 2 DM
were older and had a higher body mass index and higher
systolic blood pressure compared with the nondiabetic sub-
jects (Table 1). Diabetic patients were more likely to suffer
from hypertension, hypercholesterolemia and coronary
artery disease than the nondiabetic patients (Table 1).
eGFR was comparable between the two groups (Table 1).
Serum creatinine levels were lower in the DM group
(Table 1). Subjects with DM used more anti-aggregates,
antihypertensive agents and statins than the nondiabetic
subjects (Table 2). Most diabetic patients used
hypoglycaemic agents such as metformin (75.2%), sulfo-
nylurea (33.9%) and dipeptidyl peptidase-4 inhibitors
(24%) (Table 2).
Diabetes Metab Res Rev 2014; 30: 291–296.
DOI: 10.1002/dmrr
Diabetes Mellitus, Anaemia, Renal Function 293

Table 1. Baseline characteristics of the study population

Levels of haemoglobin and the rate of
Diabetic Nondiabetic anaemia
(n = 445) (n = 445) p
Male gender [n (%)] 401 (90) 395 (89) 0.513 Mean Hb levels were lower in subjects with DM versus those
Age (years) 63 ± 9.6 57 ± 10.1 <0.001 without DM (14.2 vs. 14.7 g/dL, respectively; p < 0.001).
2
BMI (kg/m ) 28.7 ± 5.3 26.7 ± 4.5 <0.001 The women had lower Hb levels (13.2 ± 1.1 g/dL)
Duration 6.1 ± 2.9
of DM (years) compared with the men (14.6 ± 1.1 g/dL) (p < 0.001).
Systolic BP (mmHg) 133 ± 17.6 123 ± 14.6 <0.001 In the entire group (diabetic and nondiabetic
Diastolic BP (mmHg) 79.6 ± 9.2 79.9 ± 37.9 0.839 patients), Hb levels were inversely related to age
Hypertension [n (%)] 270 (61) 84 (19) <0.001
Hypercholesterolemia 386 (87) 156 (35) <0.001 (r = 0.166; p < 0.01) and were lower in those treated
Coronary 98 (22) 21 (4.7) <0.001 with aspirin, beta blockers, ACE inhibitors, ARBs,
heart disease calcium antagonists, diuretics and statins (Figure 1). In
Gastrointestinal 16 (3.6%) 2 (0.5%) 0.001
tract diseases diabetic patients, Hb levels were related to fasting serum
Laboratory parameters glucose and diastolic blood pressure, unrelated to the
Fasting serum 148 ± 47 88 ± 8 <0.001 levels of HbA1c and inversely related to age and duration
glucose (mg/dL)
HbA1c (%) 7.7 ± 1.4 of diabetes (Table 3).
Serum creatinine 1.05 ± 0.14 1.09 ± 0.14 <0.001 Anaemia was detected in 48 (10.8%) subjects in the
(mg/dL) DM group and in only 12 (2.7%) in the nondiabetic group
eGFR (mL/min) 75 ± 13 75 ± 11 0.903
Haemoglobin (g/dL) 14.2 ± 1.2 14.7 ± 1.0 <0.001 (p < 0.001). Among diabetic patients, anaemia was found
Anaemiaa 48 (10.8%) 12 (2.7%) <0.001 in 7 out of 44 women (15.9%) and in 41 out of 401 men
(10.2%) (p = nonsignificant). Among the non- diabetic
BMI, body mass index; DM, diabetes mellitus; BP, blood pressure;
eGFR, estimated glomerular filtration rate. subjects, anaemia was found in 2 out of 50 women (4.0%)
a
Anaemia was defined when Hb is <12 g/dL for women and <13 g/dL and 10 out of 395 men (2.5%) (p = nonsignificant).
for men. Multivariate analysis demonstrated that age, gender,
history of gastrointestinal disease, use of beta blockers,
eGFR and DM were independent determinants of Hb
levels (Table 4). The odds ratio for anaemia was twofold
more amongst DM patients compared with that amongst
nondiabetic patients (Table 5). The effect of DM on Hb
Table 2. Drug therapy in the study group levels was mainly observed in men (Figure 2).
Name of Diabetic Nondiabetic
drug [n (%)] (n = 450) (n = 450) p
Aspirin
Clopidogrel
186 (41)
28 (6.3)
77 (17.3)
4 (0.9)
<0.001
<0.001
Discussion
Warfarin 8 (1.8) 6 (1.3) 0.590
Beta blockers 116 (26) 35 (8) <0.001 We found that diabetic subjects with normal renal function
ACE inhibitors 183 (41) 47 (11) <0.001 have lower levels of Hb and are more likely to suffer from
ARB 69 (15.5) 17 (3.8) <0.001
Calcium 86 (19) 24 (5.4) <0.001
antagonists
Alpha blockers 51 (11.5) 22 (5) <0.001
Diuretics 86 (19) 35 (8) <0.001
Statins 329 (74) 129 (29) <0.001
Hypoglycaemic
agents
No treatment 59 (13)
One agent 169 (38)
Two agents 161 (31)
Three or 56 (13)
more agents
Metformin 335 (75.2)
Sulfonylurea 151 (33.9)
DPP4 inhibitor 107 (24)
GLP-1 analogue 13 (2.9)
Prandase 5 (1.12)
Rosiglitazone 0
Insulin 52 (11.7)

ACE, angiotensin converting enzyme; ARB, angiotensin receptor Figure 1. Haemoglobin levels according to users (yes) and
blocker; DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. nonusers (no) of various drugs

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2014; 30: 291–296.
DOI: 10.1002/dmrr
294 C. Grossman et al.

Table 3. Correlation between haemoglobin levels and continu-

ous variables

Correlation (r) for Correlation (r) for

diabetic patients nondiabetic patients
Age 0.288* 0.029
Body mass index 0.029 0.110*
Systolic blood 0.012 0.158*
pressure
Diastolic blood 0.179* 0.096*
pressure
Fasting serum 0.182* 0.007 Figure 2. Haemoglobin levels in men and women with (DM+)
glucose and without (DM ) diabetes mellitus
eGFR 0.158* 0.026
HbA1c 0.046 —
Duration of 0.206* —
2 DM was associated with anaemia. Indeed, the diabetic
diabetes mellitus
subjects were older than the nondiabetic subjects, and
eGFR, estimated glomerular filtration rate. Hb levels were inversely related to age, but the odds ratio
*p < 0.05. for anaemia in subjects with type 2 DM was 2.15 higher
than that in nondiabetic subjects, even after adjustment
Table 4. Multiple linear regression estimating the relationship for age.
between haemoglobin and diabetes mellitus adjusted for other Our diabetic patients were not newly diagnosed as the av-
risk factors
erage duration of DM was 6 years, but they still had normal
Variables b SE beta t p renal function. An inverse correlation was found between
duration of the disease and Hb levels suggesting that in
Age 0.15 0.004 0.139 3.47 0.001
Gender 1.39 0.112 0.377 12.5 <0.001 prolonged diseases, the risk of anaemia may be even higher.
Gastrointestinal 0.609 0.242 0.076 2.52 0.012 Anaemia in diabetic patients is usually attributed to renal
tract diseases failure. The failure to increase erythropoietin levels in
Beta blocker 0.194 0.096 0.065 2.09 0.044
eGFR 0.005 0.003 0.053 1.48 0.140 response to a decline in Hb levels as a result of kidney
Diabetes mellitus 0.306 0.077 0.135 3.98 <0.001 damage involves the tubulointerstitium [18,24–27]. This
mechanism is common in chronic renal failure of any
eGFR, estimated glomerular filtration rate.
cause [28] but appears to be more pronounced in
diabetic nephropathy [3].
Table 5. Multiple logistic regression analysis estimating the Other mechanisms have been suggested to explain the
relationship between anaemia and diabetes mellitus adjusted
for other risk factors link between diabetes and anaemia in the early stages of
renal dysfunction. These include systemic inflammation,
Variables OR 95% CI p autonomic neuropathy and reduced red cell survival
Age 1.08 1.05–1.12 <0.001 [29–31]. In addition, anaemia may be attributed to drug
Gender 0.68 0.30–1.51 0.342 treatment. Rosiglitazone and metformin are known to
Gastrointestinal 3.78 1.16–12.31 0.027
induce anaemia [12–14]; however, in our study, none of
tract disease
Beta blocker 1.69 0.92–3.10 0.089 the subjects were treated with rosiglitazone, and the use
eGFR 1.01 0.98–1.04 0.426 of metformin was unrelated to Hb levels. Thus, we cannot
Diabetes mellitus 2.15 1.07–4.31 0.032
relate the anaemia to hypoglycaemic agents. Aspirin, ACE
CI, confidence interval; eGFR, estimated glomerular filtration rate. inhibitors and ARBs are known to cause anaemia
[16,17,32,33].
Diabetic subjects in our study used more aspirin
anaemia than nondiabetic subjects. Unlike previous studies and ACE inhibitors/ARBs. Indeed, users of aspirin and
that evaluated patients in diabetic clinics, we studied ACE inhibitors/ARBs exhibited lower Hb levels than
relatively healthy subjects examined on routine yearly nonusers; however, we found in the multivariate analy-
check-ups. Even in this group, we were able to show lower sis that the use of aspirin or blockers of the renin angio-
levels of Hb and a high rate of anaemia in diabetic subjects. tensin system was not a determinant of Hb levels. Thus,
Lower Hb levels and a high rate of anaemia in diabetic pa- we cannot attribute anaemia in diabetic patients to drug
tients were observed in several studies; however, most stud- treatment. Use of beta blockers was a determinant of Hb
ies included patients in renal failure [1,21–23]. levels. We cannot explain the mechanism; however, it is
In the present study, only patients with normal renal possible that those who were treated with beta blockers
function were evaluated as the eGFR was >60 mL/min had a more severe disease and therefore lower levels
in all subjects. We showed that even in these patients type of Hb.

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2014; 30: 291–296.
DOI: 10.1002/dmrr
Diabetes Mellitus, Anaemia, Renal Function 295

A history of gastrointestinal disease was a determinant of
Hb levels. However, because we excluded subjects with iron
deficiency anaemia, it is unlikely that the anaemia in our di-
abetic patients was caused by chronic blood loss. Renal func-
tion as expressed by the eGFR was related to Hb levels.
Similar results have been demonstrated by several investiga-
tors [1,23]. However, because the diabetic subjects had the
same eGFR as the nondiabetic subjects, it is dubious to link
the lower Hb levels in the diabetic subjects to renal failure.
The difference in Hb levels between diabetic and
nondiabetic subjects was more pronounced in men than that
in women; however, the rate of anaemia was the same for
both. Thus, it seems that anaemia in diabetic patients is
not gender dependent. We do not have a single explanation
for the anaemia in diabetic patients, and it seems that the
cause of anaemia in diabetic patients is multifactorial.
Anaemia is a significant prognostic factor in diabetic
patients, as anaemic patients have an increased risk of
mortality and morbidity [34,35]. Moreover, anaemia
predicts progression of diabetic complications [36]. Anae-
mia in diabetic patients may be an integrated marker
indicating the severity of the disease.
It has not been established whether in patients with DM,
the normal values of Hb should be lower. There is no
evidence that curing anaemia improves clinical outcomes
in diabetic patients with chronic renal disease, although an
improvement in quality of life has been observed [37].
Our study has several limitations. The control group
differed from the diabetic subjects in age, weight, blood
pressure, concomitant diseases and treatment. However,
they matched in renal function, as the eGFR was the same
in both groups. Moreover, the odds ratio for anaemia was
twofold higher amongst diabetic patients compared with
that amongst nondiabetic subjects after adjustment of risk
factors. We did not measure erythropoietin levels; there-
fore, we cannot comment on the pathogenesis of anaemia.
Lower erythropoietin levels in the diabetic group would
have implied that the main pathogenesis of anaemia in
this group was early kidney damage, even before clinical
renal dysfunction could be observed.
Inflammation markers and status of autonomic dys-
function were also not available in our study. The pres-
ence of these factors could have implied an alternative
pathogenic explanation for the higher prevalence of anae-
mia in diabetic patients.
In addition, existence and quantification of albuminuria
were not assessed in the study (the information had not been
documented in most of the patients). This information is im-
portant, as it indicates early diabetic nephropathy, and having
this information available could have enabled us to assess
whether patients with early diabetic nephropathy have lower
levels of Hb or higher prevalence of anaemia. This finding
would obviously imply renal dysfunction as the main reason
for anaemia in diabetic patients.
Despite the limitations, our study is unique because it
shows lower Hb levels and a high rate of anaemia in
diabetic patients even before renal failure is detected.
The results of this study have clinical implications. Firstly, it
challenges the accepted knowledge that anaemia in diabetes
is mainly caused by renal damage, and may imply that
anaemia in DM patients may have different or additional
mechanisms. Secondly, when investigating anaemia in DM
patients, one must take into account that anaemia may be
related to the diabetes itself and may indicate severity of the
disease. This notion may suggest that when a thorough
evaluation for anaemia in diabetic patients is negative, the
anaemia can be related to the diabetes. Future studies should
assess whether curing anaemia in DM patients will improve
clinical outcomes.
Acknowledgement
The authors thank Mrs Phyllis Curchack Kornspan for her
editorial services.
Conflict of interest
The authors have nothing to disclose.

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