vol.

43
Vol. 43 No. 2 (pp. 33 - 64) 2014 / Zagreb, December 2015

no.

2
p.p.
33-64

2014. Journal of Diabetes, Endocrinology and Metabolic Diseases

VUK VRHOVAC UNIVERSITY CLINIC, ZAGREB, DAMA - DIABETOLOGY ALUMNI MEDICAL ASSOCIATION

CONTENTS

ORIGINAL RESEARCH ARTICLES

PREVALENCE OF DIABETIC NEPHROPATHY

O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi . . . . . . . . . . . . . . . . . 35

THE CONTROVERSIAL ROLE OF VARIOUS OBESITY INDICES IN

ACUTE MYOCARDIAL INFARCTION
M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković . . . . . . . . . . . . . . . 47

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS DECREASE SYSTOLIC

AND DIASTOLIC BLOOD PRESSURE IN OVERWEIGHT TYPE 2 DIABETIC
PATIENTS
A. Ljubičić Pavić, T. Bulum, K. Blaslov, J. Boras, L. Duvnjak . . . . . . . . . . . . . . . . . . 57
ISSN 0351-0042
UDC 616.379-008.67.43
 DIABETOLOGIA CROATICA

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UNIVERSITY CLINIC FOR DIABETES, ENDOCRINOLOGY AND METABOLIC DISEASES

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SOCIETY FOR DIABETES AND METABOLIC DISEASES OF THE
CROATIAN MEDICAL ASSOCIATION

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1 Urology and Nephrology Center, Mansoura University,
Mansoura, Egypt
2 Faculty of Nursing, Mansoura University, Mansoura, Egypt
3 Dasman Diabetes Institute (DDI) of Kuwait, Kuwait
4 Hamed Al-Essa Organ Transplant Center and DDI, Kuwait
PREVALENCE OF DIABETIC NEPHROPATHY
O. Gheith1,4, N. Farouk2,3, N. Nampoory4, M. Halim4, T. Al-Otaibi4
Key words: diabetic nephropathy,
outcome,
risk factors
SUMMARY
In this review, we try to highlight the prevalence of
diabetic nephropathy which is not uncommon
complication of diabetes all over the world. We aimed
to give short hints on stages of diabetic nephropathy,
the possible identified risk factors for kidney disease in
diabetes (both type 1 and type 2) and its progression.
We have reviewed around 70 papers concerning the
issue of diabetic nephropathy and the possible risk
factors for progression and potential regression in
both type 1 and 2 diabetes mellitus. Moreover, we
added a few paragraphs about diabetic nephropathy
in different countries of the world and in geriatric
population.
Corresponding author: Osama Ashry Ahmed Gheith, MD, Consultant at
Urology and Nephrology Center, Mansoura University, Mansoura, Egypt,
working at Hamed Al-Essa Organ Transplant Center, Kuwait
E-mail: ogheith@yahoo.com
Diabetologia Croatica 43-2, 2014
Original Research Article
INTRODUCTION
Diabetic nephropathy is a serious complication that
occurs in 20% to 40% of all diabetics. In the Western
world, diabetic nephropathy is the prima-
ry single cause of end-stage kidney disease (ESKD)
(1). Both type 1 and type 2 diabetes mellitus (DM) can
lead to nephropathy, but in type 2 DM, a smaller
proportion of patients progress to ESKD. Because of
the higher prevalence of type 2 DM, these patients
represent more than half of diabetics on dialysis (2).
The incidence of diabetic nephropathy as a cause of
ESKD is increasing each year (1). For clinical care and
epidemiological studies, diabetic kidney disease
(DKD) is defined by elevated urine albumin excretion
or reduced glomerular filtration rate (GFR), or both
(3).
The prevalence of diabetes around the world has
reached epidemic proportions. While diabetes is
already estimated to affect more than 8% of the global
population (nearly more than 350 million people), it is
predictable to grow to over 550 million people by the
year 2035 (4). It has been estimated that more than
40% of people with diabetes will develop chronic
kidney disease (5) including a significant number of
35
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
those who will develop ESKD requiring renal
replacement therapies (dialysis and/or transplan-
tation).
Diabetic nephropathy is uncommon if diabetes is of
less than 10-year duration. The peak incidence rates of
3% per year are on average seen 10 to 20 years after
diabetes onset, after which the rate of nephropathy
tapers off. It is worth saying that a diabetic patient free
from clinical signs of nephropathy for 20 to 25 years
has only 1% yearly chance of developing such a
complication (6). There is marked racial/ethnic and
international discrepancy in the epidemiology of
diabetic nephropathy (7, 8). Native Americans,
Hispanics (especially Mexican Americans) and
African Americans have a much higher risk of
developing ESKD than non-Hispanic whites with type
2 diabetes (7). Based on 2002 United States (US) data,
diabetes is the cause of renal disease in 44% to 45%
of incident ESKD cases, making the US rate one of the
highest worldwide (8). Internationally, there is
considerable variability among countries, with
percentages ranging from 9% in Russia to 49% in
Malaysia. This discrepancy could be explained by
differences in economic viability and governmental
infrastructures (9).
STAGES OF DIABETIC NEPHROPATHY
Diabetic nephropathy is a chronic complication of
both type 1 DM (beta cell damage, absolute lack of
insulin) and type 2 DM (insulin resistance and/or
decreased insulin secretion) (10). There are five stages
in the development of diabetic nephropathy: stage I,
glomerular filtration rate (GFR) is either normal or
increased; it lasts for around five years from the onset
of DM. The size of the kidneys is increased by nearly
20% and renal plasma flow is increased by 10%-15%,
but without albuminuria or hypertension; stage II starts
more or less two years after the onset of the disease
with thickening of basement membrane and mesangial
proliferation with normalization of GFR but without
clinical signs of the disease. Many patients remain in
this stage until the end of their life; stage III represents
the first clinically detectable sign of glomerular
damage and microalbuminuria (albumin 30-300
36
mg/day). It usually occurs five to ten years after the
onset of the disease with or without hypertension.
Approximately 40% of patients reach this stage; stage
IV is the stage of chronic kidney disease (CKD) with
irreversible proteinuria (>300 mg/day), decreased
GFR below 60 mL/min/1.73 m2, and sustained
hypertension; and stage V is defined when ESKD with
GFR <15 mL/min/1.73 m2 is detected. Nearly 50% of
patients require kidney replacement therapy
(peritoneal dialysis, hemodialysis or kidney
transplantation) (11). In the early stages of diabetic
nephropathy, nephromegaly and changed doppler
indicators may be the early morphological signs of
renal damage, however, proteinuria and GFR are the
best indicators of the damage degree (12).
The predictive value of microalbuminuria for the
development of kidney damage in patients with type 1
or type 2 DM was confirmed in the early 1980’s (13).
Approximately 20%-30% of the patients develop
microalbuminuria after 15 years of disease duration
and less than half develop real nephropathy (14). The
European Diabetes (EURODIAB) Prospective
Complications Study Group (15) and 18-year Danish
study (16) report overall occurrence of
microalbuminuria in patients with type 1 and type 2
DM as 12.6% (after 7.3 years) and 33%, respectively.
According to the United Kingdom Prospective
Diabetes Study (UKPDS), the annual incidence of
microalbuminuria in patients with type 2 DM in Great
Britain is 2% and the prevalence is 25% ten years after
the diagnosis (8). Proteinuria develops more
frequently in patients with type 1 diabetes (15%-40%),
usually after 15-20 years of DM duration (17), but in
patients with type 2 DM, the prevalence varies
between 5% and 20% (4).
RISK FACTORS FOR KIDNEY DISEASE IN
TYPE 1 DIABETES
Hyperglycemia is a well known risk factor for DKD
and it has been recognized that intensive glucose
control reduces the risk of DKD (4). Specifically,
during the Diabetes Control and Complications Study
(DCCT), near normalization of blood sugar decreased
the risks of incident microalbuminuria and
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
macroalbuminuria by 39% (95% CI 21%-52%) and
54% (95% CI 29%-74%), respectively, compared with
conventional therapy. Even with long-term follow up
in the observational Epidemiology of Diabetes
Interventions and Complications (EDIC) study,
participants previously assigned to DCCT intensive
therapy continued to experience lower rates of incident
microalbuminuria and macroalbuminuria with risk
reductions of 45% (95% CI 26%-59%) and 61% (95%
CI 41%-74%), respectively (18). Beneficial effects of
intensive therapy on the worsening of GFR have
become evident during long-term combined
DCCT/EDIC follow up, with risk reduction of 50%
(95% CI 18%-69%). Other risk factors for DKD in
diabetics include male sex, obesity, hypertension,
inflammation, insulin resistance, vitamin D deficiency,
and dyslipidemia (4, 8, 19). Moreover, a hereditary
component in DKD has long been recognized as some
genetic loci and polymorphisms in specific genes have
been associated with DKD.
DIABETIC KIDNEY DISEASE IN TYPE 1
DIABETES
During the last century, landmark studies of type 1
DM considered the natural history of DKD as
progressive increase of urine albumin excretion,
followed by GFR loss and development of ESKD.
Microalbuminuria was defined as albumin excretion
rate (AER) 30 to 299 mg/24 h (‘incipient
nephropathy’) progressing steadily to macro-
albuminuria with AER ≥300 mg/24 h (‘diabetic
nephropathy’). Microalbuminuric patients commonly
noted to have higher GFR ‘hyperfiltration’, while
macroalbuminuric patients showed rapid GFR loss
leading steadily to ESKD. Frequent exceptions were
observed. Specifically, albuminuria was observed to
revert, while GFR loss was observed without
albuminuria and was not always progressive.
Therefore, albuminuria and impaired GFR are not
necessary complementary, overlapping manifestations
of DKD (4).
Diabetologia Croatica 43-2, 2014
INCIDENCE OF KIDNEY DISEASE IN
TYPE 1 DIABETES
Nearly half (or slightly less) of patients with type 1
DM develop DKD during their lifetime. Albuminuria
and reduced GFR (<60 mL/min/1.73m2) are rare
during the first decade of type 1 DM diagnosis (4). In
more recent studies, the lifetime cumulative incidence
of macroalbuminuria has been described as 15%-25%,
and the cumulative incidence of microalbuminuria has
been reported as 25%-40% (19). In early studies, up to
35% of participants developed ESKD. In Finland and
in the Pittsburgh Epidemiology of Diabetes Cohort
(Pittsburgh, PA, USA), the long-term cumulative
incidence of ESKD dropped to less than 10%,
although the rate of ESKD remained higher in the
Joslin type 1 diabetes cohort (Boston, MA, USA) (20).
PROGRESSION OF KIDNEY DISEASE IN
TYPE 1 DIABETES
The progression of DKD in type 1 DM is
unpredictable. In the Joslin type 1 diabetes cohort,
29% of participants with microalbuminuria showed
reduced GFR within 12-year average follow up. The
EURODIAB type 1 diabetes study has reported that
14% of microalbuminuric patients progressed to
macroalbuminuria over 7.3-year average follow-up.
Steno type 1 diabetes cohort showed that 34% of
participants with microalbuminuria went on to develop
macroalbuminuria over 7.5-year average follow up
(19). In the DCCT/EDIC cohort, the 10-year
cumulative incidence of macroalbuminuria was 28%
in the participants who had incident microalbuminuria
(20).
In the DCCT/EDIC cohort, patients with
macroalbuminuria lost GFR at a mean rate of 5.7% per
year, and the 10-year cumulative incidence of
impaired GFR was 32%, while in patients with
microalbuminuria, the mean rate of estimated GFR
loss was 1.2% per year, and the 10-year cumulative
incidence of reduced GFR was 15%. Interestingly, in
the Joslin type 1 diabetes cohort, the “early renal
function decline” occurred in 31% of participants with
microalbuminuria and occasionally also in participants
37
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
with persistent normoalbuminuria (AER <30 mg/24
h). Such findings suggest that albuminuria and GFR
loss are linked but are not necessarily reflective of a
single, homogeneous underlying disease process (8).
REGRESSION OF KIDNEY DISEASE IN
TYPE 1 DIABETES
Microalbuminuria commonly regresses to
normoalbuminuria as reported in the Joslin type 1
diabetes cohort. The authors showed that 58% of
patients with persistent microalbuminuria regressed to
persistent normoalbuminuria over the next 6 years,
frequently without inhibitors of the renin-angiotensin-
aldosterone system (RAAS) (19). Similar results were
observed in the DCCT/EDIC (8, 19). Therefore, better
control of diabetes, hypertension and lipids was
associated with a greater likelihood of
microalbuminuria regression. Of the DCCT/EDIC
participants who developed macroalbuminuria, 52%
regressed to sustained microalbuminuria or
normoalbuminuria within 10 years, but many were
managed with RAAS inhibitors (21). Moreover,
regression of macroalbuminuria was associated with
an 89% lower risk of progressing to reduced GFR. In
the same direction, longitudinal studies of pancreas
transplantation demonstrate that the pathological
lesions of diabetic glomerulopathy can regress with
euglycemia (22).
KIDNEY DISEASE IN TYPE 2 DIABETES
The incidence of DKD and the rates of DKD
progression are less clear in type 2 DM compared with
type 1 DM, mainly due to the highly variable age at
onset, complexity of defining the exact time of
diabetes onset, and the relative scarcity of long-term
type 2 diabetes cohorts. Therefore, two of the best
characterized type 2 DM cohorts are the United
Kingdom Prospective Diabetes Study (UKPDS) and
the Pima Indian population. The UKPDS enrolled
more than 5000 participants with new-onset type 2
DM and after a median 15-year follow up, they found
that microalbuminuria (defined as persistent urine
albumin concentration ≥50 mg/L) occurred in 38%
38
and reduced GFR (defined as persistent estimated
creatinine clearance ≤60 mL/min/1.73m2) in 29% of
participants (23). Among Pima Indians, for whom the
onset and duration of diabetes are more precisely
determined due to systematic diabetes screening, the
cumulative incidence of heavy proteinuria (≥1 gram
per gram creatinine) was 50% at 20-year duration,
prior to widespread use of RAAS inhibitors. The high
rate of proteinuria in the Pima population remained
stable over time, although the incidence of ESKD had
declined (24).
In most type 2 diabetics, the prevalence of DKD at
any time point is approximately 30%-50%. Among the
US adults with diabetes (>90% type 2), the overall
prevalence of DKD was approximately 35%, ranging
from nearly 25% in patients younger than 65 to nearly
50% in those older than 65 (24). At younger ages,
microalbuminuria predominates while in older age
reduced GFR is increasingly prevalent among cases
with DKD. This finding could be explained by the
trend in using medications that reduce albuminuria,
such as glucose-lowering medications and RAAS
inhibitors.
However, the phenotype of reduced GFR with
normoalbuminuria has been increasingly recognized
in type 2 DM. In population-based studies of diabetes
in the United States and Australia, 36%-55% of
individuals with reduced GFR did not have concurrent
microalbuminuria or macroalbuminuria. Frequently,
non-albuminuric reduced GFR was observed in the
absence of diabetic retinopathy, suggesting underlying
processes other than diabetic glomerulopathy. In the
UKPDS, female gender, advanced age and insulin
resistance were risk factors for reduced GFR but not
microalbuminuria, while male gender, adiposity,
hyperglycemia and dyslipidemia were risk factors for
microalbuminuria but not reduced GFR (22). Higher
blood pressure was a risk factor for both reduced GFR
and microalbuminuria.
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
PROGRESSION OF KIDNEY DISEASE IN
TYPE 2 DIABETES
The progression and regression of established DKD
is highly variable in type 2 DM. In the UKPDS,
evolution from microalbuminuria to macroalbu-
minuria occurred at a rate of 2.8% per year, and
change from macroalbuminuria to elevated plasma
creatinine or ESKD occurred at a rate of 2.3% per year
(25). Similar to what happens with type 1 DM, loss of
GFR can occur at any level of urine albumin excretion
but tends to be more rapid with greater urine albumin
excretion. At the diagnosis of type 2 DM, 7.3% of
patients had microalbuminuria or worse, rising to
17.3% after 5 years, 24.9% after 10 years and 28.0%
after 15 years (25).
HEALTH CONSEQUENCES OF DIABETIC
KIDNEY DISEASE
The high mortality risk observed among people with
both types 1 and 2 DM is largely confined to those
with evidence for DKD because it is associated with a
number of interrelated cardiovascular diseases,
including micro- and macroangiopathies.
DIABETIC KIDNEY DISEASE IN
DIFFERENT COUNTRIES
Diabetic nephropathy is more frequent in African
Americans, Asian Americans, and native Americans
(26). Progressive kidney disease is more frequent in
Caucasian patients with type 1 than type 2 DM,
although its overall prevalence in the diabetic
population is higher in patients with type 2 DM
because this type of DM is more prevalent (27). The
occurrence of diabetic nephropathy in Pima Indians is
very interesting, indeed. Craig et al. have reported that
around 50% of Pima Indians with type 2 DM
developed nephropathy after 20 years of the disease,
and 15% of them were already in the terminal stage of
kidney failure (28). In the United States, the
occurrence of diabetic nephropathy in patients
beginning kidney replacement therapy doubled in the
Diabetologia Croatica 43-2, 2014
late 1990s (28). Fortunately, the trend has been
decreasing, most likely due to better prevention and
earlier diagnosis and treatment of DM (29).
In the USA, 25.6 million adults (11.3%) aged 20
years and more had diabetes in 2011, with the
prevalence increasing in older age groups (26.9% of
people aged ≥65). However, nearly 3% of newly
diagnosed patients with type 2 DM have overt
nephropathy. Among people with diabetes, the
prevalence of DKD remained stable (3).
Approximately 44% of new patients entering dialysis
in the United States are diabetics. Early diagnosis of
diabetes and early intervention are critical in
preventing normal progression to renal failure seen in
many type 1 and a significant percentage of type 2
diabetics. The prevalence of diabetes is higher in
certain racial and ethnic groups, affecting
approximately 13% of African Americans, 9.5% of
Hispanics, and 15% of native Americans, primarily
with type 2 DM (30, 31). Nearly 20% to 30% of all
diabetics will develop evidence of nephropathy,
although a higher percentage of type 1 patients
progress to ESKD.
Epidemiological differences are recorded among
European countries, mainly Germany. The proportion
of patients admitted for renal replacement therapy is
higher than that reported from the United States. In
Heidelberg (southwest of Germany), nearly 60% of
patients admitted for renal replacement therapy in
1995 had diabetes, with the majority (90%) of type 2
DM. An increase in ESKD secondary to type 2 DM
has been noted even in countries known to have low
incidences of type 2 DM, such as Denmark and
Australia. The exact incidence and prevalence in Asia
are not currently available (3).
Pavkov et al. (32) report that diabetic nephropathy
affects males and females equally, and it rarely
develops before 10-year duration of type 1 DM. The
role of age in the development of DKD is unclear
although the mean age of patients who reach ESKD is
about 60 years and the incidence of DKD is higher
among elderly persons who have had type 2 diabetes
for a longer time. In Pima Indians with type 2 DM, the
earlier the onset of diabetes, the higher is the risk of
progression to ESKD.
39
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
The incidence and severity of diabetic nephropathy
are 3- to 6-fold higher in blacks than in whites.
Similarly, diabetic nephropathy is more common
among Mexican Americans and Pima Indians with
type 2 DM. This suggests that socioeconomic factors
such as diet, poor control of hyperglycemia,
hypertension, and obesity have a primary role in the
development of diabetic nephropathy. Familial
clustering may be one of the important factors in these
populations.
Bhalla et al. (33) report that in patients with type
2 DM, racial/ethnic minorities were more likely to
have proteinuric DKD and less likely to
have nonproteinuric DKD.
Diabetic nephropathy has become an important
clinical and public health challenge, as reported by de
Boer et al. (3), who estimated the disease burden in the
US adult population aged 20 years or older using data
from the National Health and Nutrition Examination
Survey. In a cross sectional study including 32,208
type 2 DM patients from 33 countries, Parving et al.
report on the prevalence of micro-/macroalbuminuria
to be 38.8% and 9.8%, respectively (34). Asian and
Hispanic patients had the highest prevalence of
microalbuminuria (43.2% and 43.8%) and
macroalbuminuria (12.3% and 10.3%), while
Caucasians had the lowest microalbuminuria (33.3%)
and macroalbuminuria (7.6%). Twenty-two percent of
patients had compromised renal function (GFR <60
mL/min/1.73 m2). Unnikrishnan et al. (35) report that
the prevalence of overt nephropathy and micro-
albuminuria was 2.2% and 26.9%, respectively, among
type 2 diabetics in urban Asian Indians. Among 8,897
Japanese type 2 DM patients from 29 medical clinics
or general/university-affiliated hospitals from different
areas, the prevalence of microalbuminuria and
decreased GFR (<60 mL/min/1.73 m2) was 31.6% and
10.5%, respectively (36).
In the US population, the Pathways Study-across-
sectional analysis among 2,969 primary care diabetics
of a large local health maintenance organization
observed the racial/ethnic differences in early diabetic
nephropathy despite comparable access to diabetes
care. Among non-hypertensives, microalbuminuria
was twofold greater (odds ratio 2.01; 95% confidence
40
interval (CI) 1.14-3.53) and macroalbuminuria was
threefold greater (odds ratio 3.17; 95% CI 1.09-9.26)
for Asians as compared with whites. Among
hypertensive patients, adjusted odds of micro-
albuminuria were greater for Hispanics (odds ratio
3.82; 95% CI 1.16-12.57) than whites, whereas
adjusted odds of macroalbuminuria were threefold
greater for blacks (odds ratio 3.32; 95% CI 1.26-8.76)
than for whites (37).
What is new is the recent unreasonable rise in the
prevalence of metabolic syndrome (38) and of type 2
DM (39) worldwide, which is extremely pronounced
in Asian countries (39), especially in India, the
‘diabetes capital of the world’ (40-43). Indian diabetics
have a propensity to have insulin resistance, higher
waist circumference despite lower body mass index, as
well as lower adiponectin and higher inflammatory
markers (43). The prevalence of overt diabetes is
particularly high in Indian elderly (44), in addition to
prediabetes and overt diabetes in the young (44, 45),
and consequently diabetic nephropathy, especially in
rural populations of India (46-50). The estimated
overall incidence rate of chronic kidney disease and
ESKD in India is currently 800 per million population
and 150-200 per million population, respectively (50).
Of great interest is the fact that the risks of impaired
fasting glucose and impaired glucose tolerance are
markedly higher in citizens of a South-East Asian
origin compared with the local populations of
European origin (51). Furthermore, the prevalence of
any type of chronic kidney disease and its rate of
progression, and specifically also of diabetic
nephropathy, is significantly higher in the citizens of
Asian origin, as observed both in the UK (54) and
Canada (53), presumably as the result of different
genetics and/or lifestyle and the lack of awareness of
kidney complications of diabetes (54).
As many as six Arabic-speaking countries are among
the world’s leaders in terms of type 2 DM prevalence;
these countries are Kuwait, Lebanon, Qatar, Saudi
Arabia, Bahrain, and the United Arab Emirates (UAE).
Rapid economic growth brings with it great
opportunities for improvements in the infrastructure
(e.g., health care and education), it also carries with it
the burden of greater reliance on mechanization, a
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
proliferation of Western-style fast food, access to
cheap migrant labor, and as elsewhere, greater
opportunities for sedentary lifestyles, especially in the
young (55).
In a cross-sectional study from Egypt, 42% of
diabetics had nephropathy (56); in Jordan, 33% of
diabetics at a national diabetes center had nephropathy
(57); and at a diabetic clinic in Libya, 25% of patients
had nephropathy (58).
GERIATRICS AND DIABETIC
NEPHROPATHY
Increase in the prevalence of diabetic nephropathy
also derives directly from the growth in the prevalence
of diabetic nephropathy among individuals aged 65
years and older. Individuals older than 65 are unduly
affected by diabetes and related ESKD. According to
data from the National Health and Nutrition
Examination Survey, diabetes prevalence was 26.9%
among people aged ≥65 (59, 60). The prevalence of
diabetic nephropathy increased from 7.1% in 1988-
1994 to 8.6% in 1999-2004 and 10.7% in 2005-2008
among individuals aged 65 years and older (3, 61).
Recent data also revealed that the adjusted point
prevalence rates per million population of reported
diabetes-related ESKD for individuals aged 60-69 and
≥70 were 410.3 and 475.7 in whites and 1439.9 and
1471.5 in Africans (62, 63).
One of the challenges of managing the elderly with
diabetic nephropathy is that they may develop more
complications, especially heart, eye, and peripheral
vascular diseases. In their 2011 National Diabetes Fact
Sheet, the Centers for Disease Control (CDC) reported
that in 2004, heart disease and prior stroke were noted
on 68% and 16% of diabetes-related death certificates,
respectively, among people aged 65 years or older
(59). Moreover, the CDC indicated that, in 2005, 27%
of adults with diabetes aged ≥75 reported some degree
of visual impairment compared with 15% of diabetic
patients aged 18-44 (59). Individuals aged ≥65
account for 55% of diabetic subjects who had
nontraumatic lower extremity amputations (64).
Caring for elderly patients with diabetic renal disease
imposes a huge financial burden on governments and
Diabetologia Croatica 43-2, 2014
family members. For example, the American Diabetes
Association indicated that the total estimated cost of
diabetes in 2007 was $174 billion, including $58
billion to treat diabetes-related chronic complications
(65).
Diabetic nephropathy in the elderly is mainly due to
type 2 DM and its distribution is uneven among racial
groups. American-Indians, African-Americans, and
Mexican-Americans have a greater incidence than
Caucasians by as much as three to one depending on
the minority cohort selected for comparison (63).
Nearly all studies demonstrating beneficial effects of
metabolic and blood pressure controls on DKD have
been performed in young to middle-aged cohorts.
Importantly, the management of DKD in older people
is frequently based on extrapolations of data gathered
in selected and motivated younger people. Moreover,
people older than 70 have been virtually excluded in
trials supporting major US practice guidelines for the
use of angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers in chronic kidney
disease. In managing diabetes and diabetic
nephropathy in the elderly, clinicians should keep in
mind several key points:
1) elderly diabetic patients constitute a diverse
group expressing various clinical and functional
situations;
2) the American Geriatric Society Panel on
Improving Care for Elders with Diabetes
recommends that treatment of elderly patients
with diabetes focus on specific problems and
priorities (66);
3) the American Geriatric Society has also
introduced the concept of time horizon for the
benefits of certain treatments. Glycemic control
may take as long as 8 years to have positive
results on microvascular complications. Benefits
of good blood pressure and lipid control may not
be noticeable before 2 or 3 years (67);
4) many elderly patients with diabetes are fragile
and are also at a greater risk of developing
several common geriatric syndromes, such as
depression, cognitive impairment, urinary
incontinence, injurious falls, and persistent pain.
The Assessing Care of Vulnerable Elders
41
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY

(ACOVE) project defines a frail elderly patient 6) elderly diabetic patients may be susceptible to
as a vulnerable person who is older than 65 and nephrotoxic agents such as radiocontrast;
is at an increased risk of death or functional specific caution should be taken in preventing
decline within 2 years (67); and monitoring radiocontrast induced
5) in consequence, renoprotection in a geriatric nephropathy.
population should be tailored according to
In conclusion, diabetic nephropathy is not
patient’s autonomy, degree of frailty, life
uncommon complication of diabetes (types 1 and 2) all
expectancy, comorbidity index, and the stage of
over the world and among geriatric population.
diabetic nephropathy; and

42
 O. Gheith, N. Farouk, N. Nampoory, M. Halim, T. Al-Otaibi / PREVALENCE OF DIABETIC NEPHROPATHY
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46
1 Department of Internal Medicine and Dialysis, Zagreb-East Original Research Article
Health Center, Zagreb, Croatia;
2 Coronary Care Unit, Sestre milosrdnice University Hospital
Center, Zagreb, Croatia;
3 Cardiac Catheterization Laboratory, Sestre milosrdnice
University Hospital Center, Zagreb, Croatia;
4 Department of Kinesiologic Anthropology, Faculty of
Kinesiology, Zagreb, Croatia

THE CONTROVERSIAL ROLE OF VARIOUS OBESITY INDICES

IN ACUTE MYOCARDIAL INFARCTION
M. Mornar Jelavić1, Z. Babić2, H. Pintarić3, M. Mišigoj-Duraković4

Key words: obesity,
myocardial infarction,
percutaneous coronary intervention,
sick leave
SUMMARY
This prospective study (September 2011-September
2012) including 250 patients investigated the
controversial role of obesity indices in clinical severity
and prognosis of acute ST-elevation myocardial
infarction (STEMI) treated with primary percutaneous
coronary intervention. Study patients were grouped
according to obesity indices: body mass index (BMI)
(<25.0, 25.0-29.9 and ≥30.0 kg/m²), waist
circumference (WC) (<102/88 and ≥102/88 cm),
waist-to-hip ratio (WHR) (<0.90/0.85 and ≥0.90/0.85)
and waist-to-height ratio (WHtR) (<53/49, 53/49-
62/57 and ≥63/58). The groups were analyzed by the
baseline, severity (clinical, laboratory, echo-
cardiography, coronary angiography, and in-hospital
complications) and prognostic parameters (major
Corresponding author: Marko Mornar Jelavić, MD, Department of Internal
Medicine and Dialysis, Zagreb-East Health Center, Ninska 10, HR-10000
Zagreb, Croatia
E-mail: mjelavic@yahoo.com
adverse cardiovascular events, and sick leave during
12-month follow up). While BMI <25.0 kg/m2
increased and BMI 25.0-29.9 kg/m2 reduced the risk of
dyspnea, WHR ≥0.90/0.85 increased the risk of
significant proximal/middle coronary segment stenosis
and WHtR ≥63/58 increased the risk of heart failure
and total in-hospital complications (p<0.05). In
conclusion, WHR and for the first time used WHtR are
superior to BMI in predicting acute STEMI severity,
while WC has no influence on it. Obesity indices have
no impact on prognosis.
INTRODUCTION
Overweight and obesity are one of the major public
health problems. Obesity prevalence in Europe has
reached epidemic proportions (up to 28.3% of men
and 36.5% of women) with higher prevalence rates in
Central, Eastern, and Southern Europe than those in
Western and Northern Europe (1,2). Obesity is an
independent risk factor for the development of
cardiovascular disease (CVD), including coronary
artery disease (CAD) and heart failure. It is frequently

Diabetologia Croatica 43-2, 2014 47

 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION
associated with arterial hypertension, diabetes mellitus
type 2 and atherogenic dyslipidemia, as well as with an
increased risk of all-cause morbidity and mortality (3).
Measurement of body mass index (BMI), waist
circumference (WC), waist-to-hip ratio (WHR) and
waist-to-height ratio (WHtR) is a primary method for
diagnosing obesity. While BMI determines overall
obesity, other obesity indices are related to central
obesity. Also, they are stronger predictors of CVD risk
than BMI (4-6). It is not surprising because central
obesity correlates with excessive visceral fat, which is
directly associated with insulin resistance and
compensatory hyperinsulinemia, dyslipidemia and
inflammatory states that synergistically lead to smooth
muscle cell proliferation, calcium and cholesterol ester
deposition in the artery, and finally to atherosclerotic
vascular disease (7-9).
In subjects with acute myocardial infarction (MI),
there is a positive association of increasing abdominal
obesity with higher mortality, as well as an inverse
association between BMI and mortality (‘obesity
paradox’). The possible explanation could be that BMI
does not adequately discriminate the difference
between body fat (especially abdominal) and lean
muscle mass (5).
The main objectives of this study were to evaluate
the severity and prognosis of acute ST-elevation
myocardial infarction (STEMI) in patients with
various obesity indices and treated with primary
percutaneous coronary intervention (PCI). Also, for
the first time, we investigated the involvement of
coronary artery (CA) segments with significant
stenosis, as well as sick leave duration (SLD) in these
patients.
PATIENTS AND METHODS
We prospectively analyzed 250 consecutive patients
with acute STEMI treated with primary PCI in
Department of Cardiology, Sestre milosrdnice
University Hospital Center (September 2011-2012).
The inclusion criteria were presenting within 12 h
from the onset of symptoms (history of chest
pain/discomfort lasting for 10-20 minutes or more, not
48
responding fully to nitroglycerine), persistent ST-
segment elevation on electrocardiography (ECG) in at
least two consecutive leads, or (presumed) new left
bundle branch block (LBBB), and elevated cardiac
laboratory biomarkers (cardiac troponin T (cTnT) and
creatine kinase (CK)). The diagnosis of acute STEMI
was established and primary PCI performed using the
criteria of the European Society of Cardiology (10,11).
The study was approved by the Ethics Committee of
the Sestre milosrdnice University Hospital Center,
Zagreb, Croatia.
After primary PCI, patients were grouped according
to the obesity indices as follows: BMI (<25.0, 25.0-
29.9 and ≥30.0 kg/m² for normal weight, overweight
and overall obesity, respectively), WC (<102/88 and
≥102/88 cm for normal weight and central obesity in
males/females, respectively), WHR (<0.90/0.85 and
≥0.90/0.85 for normal weight and central obesity in
males/females, respectively) and WHtR (<53/49,
53/49-62/57 and ≥63/58 for normal weight,
overweight and central obesity in males/females,
respectively) (5,12-14).
The groups were analyzed by baseline, as well as
severity and prognostic parameters of acute STEMI as
follows:
Baseline demographic and medical history
parameters included gender, age, arterial hypertension,
dyslipidemia (elevated triglycerides and/or low HDL
cholesterol), hyperglycemia, smoking status, known
family history of cardiovascular events (MI,
cerebrovascular insult), previous MI, previous PCI and
coronary artery bypass grafting (CABG). For the
diagnosis of dyslipidemia, hypertension and
hyperglycemia, we used the criteria published by the
National Cholesterol Education Program – Adult
Treatment Panel III group (12), as follows:
Hypertriglyceridemia: triglycerides ≥150 mg/dL (1.7
mmol/L), or on medication for elevated triglycerides;
Low HDL-cholesterol: <40 mg/dL (1.04 mmol/L) in
males or <50 mg/dL (1.29 mmol/L) in females, or on
medication for low HDL-cholesterol;
Hypertension: blood pressure ≥130/85 mm Hg, or on
medication for hypertension;
 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION
Hyperglycemia: fasting plasma glucose ≥100 mg/dL
(5.6 mmol/L), or on medication for hyperglycemia;
The severity of acute STEMI was estimated by
clinical presentation (angina pectoris, dyspnea, and
duration of hospitalization), in-hospital complications
(arrhythmias, conduction disturbances, reperfusion
arrhythmias, heart failure, cardiogenic shock, cardiac
arrest, mechanical ventilation, reinfarction, repeated
PCI, mortality, and total in-hospital complications),
coronary angiography, laboratory (maximal cTnT,
CK) and echocardiography (left ventricular ejection
fraction, LVEF) findings.
Coronary angiography was performed by applying a
monoplane system (Axiom Artis, Siemens, Erlangen,
Germany) by a common technique, as recommended
in current guidelines (11). Patients received 70 IE/kg
unfractionated heparin, 300 mg aspirin, a loading dose
of 600 mg clopidogrel, and a GPIIb/IIIa inhibitor
according to judgment of interventional cardiologist.
CA stenosis of more than 50% was considered
clinically significant. We analyzed the number of
significantly narrowed CAs, number, length and
diameter of stents used. Additionally, for the first time,
we analyzed significantly stenosed segments of CAs.
For that purpose, and according to the modified
American Heart Association classification (15), CAs
were divided into 16 segments. Segments were
classified in two groups, as follows:
Proximal and middle CA segments: segment 1 (right
coronary artery (RCA), proximal), segment 2 (RCA,
mid), segment 5 (main stem), segment 6 (left anterior
descending coronary artery (LAD), proximal),
segment 7 (LAD, mid), segment 9 (first diagonal, D1),
segment 11 (left circumflex artery (LCX), proximal),
segment 12 (obtuse marginal, OM);
Distal CA segments: segment 3 (RCA, distal),
segment 4 (right posterior descendens), segment 8
(LAD, distal), segment 10 (second diagonal, D2),
segment 13 (LCX, distal), segment 14 (LCX,
posterolateral branch), segment 15 (LCX,
posterodescendens branch), segment 16 (RCA,
posterolateral branch).
Diabetologia Croatica 43-2, 2014
Serum CK activity was measured by
spectrophotometry (Olympus 680, Beckman Coulter
Inc., California, USA). Serum cTnT levels were
measured by electrochemiluminescence (ECL) assay
(Cobas e411, Roche Diagnostics, Sussex, UK). During
hospital stay, echocardiography was performed in all
patients (Acuson Sequoia 512, Siemens, Munich,
Germany) according to the clinical standards and
current echocardiography guidelines (16).
The prognosis of acute STEMI was estimated using
MACE parameters (reinfarction, CA restenosis and
new stenosis, cardiac and non-cardiac
rehospitalization, CVI, urgent CABG, mortality, total
MACE) during 12-month follow up. Data were
collected by medical examination, checking medical
documentation, or telephone contact with patients,
family members or home physicians. In addition,
during the same follow up period, we collected data on
SLD of working population.
Statistical analysis
Qualitative data were expressed as absolute number
and percentage. We used χ2-test with Yates correction
for comparison and analysis. Quantitative data were
expressed as median and corresponding interquartile
range. Differences between two groups were tested by
Mann-Whitney U test. Differences among three
groups were tested by nonparametric analysis of
variance (Kruskal-Wallis ANOVA). Logistic
regression analysis was used to investigate the
relationship between one dependent and one or more
independent variables that may influence or predict the
value of the dependent variable. The level of statistical
significance was set at p<0.05. Processing was done
using the STATISTICA 6.0 for Windows software.
RESULTS
Among 250 patients, there were 72 (28.8%) patients
with BMI ≥30.0 kg/m², 149 (59.6%) with WC ≥102/88
cm, 222 (88.8%) with WHR ≥0.90/0.85 and 81
(32.4%) with WHtR ≥63/58. We recorded the
following results:
49
 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION
1) BMIs ≥30.0 kg/m² had the highest rates of
hypertension (34 (56.7%) vs. 84 (71.2%) vs. 63
(87.5%), p=0.000) and dyslipidemia (40
(66.7%) vs. 88 (74.6%) vs. 62 (86.1%),
p=0.030). Also, they had longest hospitalization
and widest stents, while BMIs <25.0 kg/m2 had
the highest rates of dyspnea (Table 1).
2) WCs ≥102/88 cm were more frequently females
(14 (13.9%) vs. 59 (39.6%), p=0.000) and had
higher rates of hypertension (54 (53.5%) vs. 127
(85.2%), p=0.000). In comparison with WCs
<102/88 cm, all parameters of severity and
prognosis were without significant differences
(Table 1).
3) WHRs ≥0.90/0.85 were more frequently males
(8 (28.6%) vs. 169 (76.1%), p=0.000) and had
higher rates of dyslipidemia (17 (60.7%) vs. 173
(77.9%), p=0.044). Also, they had higher rates
of significantly stenosed proximal/middle CA
segments (Table 2).
4) WHtRs ≥63/58 were more frequently females
(10 (20%) vs. 18 (15.1%) vs. 45 (55.6%),
p<0.0001) and had the highest rates of arterial
hypertension (29 (58%) vs. 79 (66.4%) vs. 73
(90.1%), p<0.0001), heart failure and total in-
hospital complications (p<0.05). Other baseline
and parameters of severity, as well as all
prognostic parameters were without significant
differences (Table 2).
5) BMI <25.0 kg/m2 increased (odds ratio (OR)
2.0, confidence interval (CI) [1.09-3.68],
p=0.03) and BMI 25.0-29.9 kg/m2 reduced the
risk of dyspnea (OR 0.52, CI [0.30-0.91],
p=0.02). WHtR ≥63/58 adjusted for
hyperglycemia increased the risk of heart failure
(OR 2.05, CI [1.13-3.71] p=0.02) and total in-
hospital complications (OR 1.94, CI [1.13-3.33]
p=0.02), while WHR ≥0.90/0.85 adjusted for
gender increased the risk of proximal/middle
CA segments stenosis (OR 3.34, CI [1.13-9.86],
p=0.03). The number of significantly stenosed
CAs, adjusted for LVEF and distal CA segment
stenosis increased the risk of total MACE (OR
1.79, CI [1.17-2.77], p=0.01).
50
DISCUSSION
The main finding of this study was that WHR and
WHtR proved superior to BMI in predicting clinical
severity (significant proximal/middle CA segment
stenosis, heart failure and total in-hospital
complications vs. dyspnea), while WC had no
influence on it. Obesity indices had no influence on
prognosis. Finally, the number of significantly
stenosed CAs increased the risk of total MACE, which
is consistent with literature data (17).
Several studies have reported a paradoxical clinical
effect of elevated BMI on improved survival after PCI
in patients with acute STEMI, i.e. the overall ‘obesity
paradox’ (18-21). Overweight and obese patients had
wider stents, normal LVEF, lower CK levels, in-
hospital and overall mortalities, as well as lower rates
of MACE during 12-month follow up (22). Patients
with normal BMI had more serious CA calcification,
smallest vessel size, and thus a less favorable
artery/device ratio; they had highest rates of in-
hospital mortality and MACE 12 months after primary
PCI (23-27). Other obese patients with acute STEMI
had similar PCI characteristics and MACE as normal
weight and overweight patients (28). Overweight and
obesity did not result in significantly greater
myocardial damage and left ventricular dysfunction,
either in the acute phase or 6 months after acute MI
treated with primary PCI (29). Iakobishvili et al. and
Li et al. found no significant differences in infarct size,
and in 3-month and 1-year outcomes among the BMI
categories with acute STEMI and primary PCI (30,31).
The ‘obesity paradox’ could explain why we found no
significant differences among normal weight,
overweight and overall obese patients in prognosis
(MACE and SLD), as well as that of the severity
parameters, normal weight increased and overweight
reduced the risk of dyspnea.
The presence of increased WC is associated with
greater myocardial necrosis and worsened LVEF in
patients with acute MI (32,33). However, the
protective role of increased WC in the presence of
significant angiographic CAD, i.e. central ‘obesity
paradox’ has been described (34). Subcutaneous fat
component is probably mainly responsible for the
 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION

Table 1. Severity and prognosis of acute ST-elevation myocardial infarction according to BMI (kg/m²) and WC (cm)

BMI BMI BMI WC WC

PARAMETERS <25.0 25.0-29.9 ≥30.0 p <102/88 ≥102/88 p
(n = 60) (n = 118) (n = 72) (n=101) (n=149)

Angina pectoris, n (%) 60 (100) 114 (96.6) 71 (98.6) 0.283 99 (98) 146 (98) 0.985
Clinical
Dyspnea, n (%) 25 (41.7) 27 (22.9) 23 (31.9) 0.032 27 (26.7) 48 (32.2) 0.353
presentation
Hospitalization (days) 9 (2-31) 8.5 (2-21) 9 (6-32) 0.028 8 (2-30) 9 (3- 32) 0.126
Arrhythmias, n (%) 11 (18.3) 20 (17) 12 (16.7) 0.964 14 (13.9) 29 (19.5) 0.250
Conduction abnorm., n (%) 6 (10) 6 (5.1) 4 (5.6) 0.422 4 (4) 12 (8.1) 0.194
Heart failure, n (%) 17 (28.3) 25 (21.2) 22 (30.6) 0.306 20 (19.8) 44 (29.5) 0.084
Cardiogenic shock, n (%) 6 (10) 8 (6.8) 4 (5.6) 0.598 7 (6.9) 11 (7.4) 0.892

In-hospital Cardiac arrest, n (%) 9 (15) 16 (13.6) 11 (15.3) 0.937 12 (11.9) 24 (16.1) 0.350
complications Mechanical ventilation, n (%) 2 (3.3) 5 (4.2) 3 (4.2) 0.955 2 (2) 8 (5.4) 0.180
Reinfarction, n (%) 0 (0) 1 (0.8) 0 (0) - 0 (0) 1 (0.7) -
Re-PCI, n (%) 1 (1.7) 3 (2.5) 0 (0) - 1 (1) 3 (2) -
Mortality, n (%) 6 (10) 6 (5.1) 7 (9.7) 0.365 10 (9.9) 9 (8.3) 0.258
Total, n (%) 27 (45) 45 (38.1) 32 (44.4) 0.575 36 (35.6) 68 (45.6) 0.116
Max. cTnT (ng/mL) 3.7 (0-10) 3 (0-10) 2.9 (0-10) 0.642 3.5 (0-10) 2.8 (0-10) 0.246
Laboratory 1915.5 1779 1900 2571 1701
Max. CK (U/L) 0.952 0.296
(107-15617) (25-13769) (85-14094) (70-15617) (25-14094)

Left ventricle ejection fraction

ECHO 50 (28-70) 53 (25-70) 50 (30-76) 0.949 50 (25-64) 50 (28-76) 0.521
(%)
Stenosed CAs 2 (1-4) 2 (1-4) 1 (1-3) 0.456 1 (1-4) 2 (1-4) 0.399
≥2 stenosed CAs, n (%) 33 (55) 60 (50.8) 35 (48.6) 0.761 48 (47.5) 80 (53.7) 0.339
Number of stents 1 (1-4) 1 (1-3) 1 (1-3) 0.266 1 (1-4) 1 (1-3) 0.269
Stent diameter (mm) 3 (2.5-4) 3.5 (2.3-4) 3.5 (2.8-4) 0.000 3 (2.8-4) 3.5 (2.3-4) 0.184
Coronary
angiography Stent length (mm) 18 (8-36) 20 (8-38) 20 (8-38) 0.099 18.5 (8-38) 20 (8-38) 0.060
Proximal/middle CAs
54 (90) 106 (90.6) 66 (91.7) 0.944 88 (88) 138 (92.6) 0.217
segment stenosis, n (%)
Distal CAs segments
27 (45) 47 (40.2) 23 (31.9) 0.289 38 (39.2) 59 (39.6) 0.800
stenosis, n (%)
Reinfarction, n (%) 1 (1.9) 0 (0) 1 (1.5) - 1 (1.1) 1 (0.7) -
Restenosis, n (%) 2 (3.8) 4 (3.8) 1 (1.5) 0.655 4 (4.4) 3 (2.2) 0.349
New stenosis, n (%) 1 (1.9) 3 (2.8) 3 (4.4) 0.712 4 (4.4) 3 (2.1) 0.349
Cardiac rehosp., n (%) 8 (15.1) 18 (17) 11 (16.2) 0.954 13 (14.3) 24 (17.6) 0.502
MACE Non-cardiac rehosp., n (%) 5 (9.4) 3 (2.8) 1 (1.5) 0.059 4 (4.4) 5 (3.7) 0.786
CVI, n (%) 1 (1.9) 0 (0) 0 (0) - 0 (0) 1 (0.7) -
Urgent CABG, n (%) 1 (1.9) 3 (2.8) 2 (2.9) 0.925 1 (1.1) 5 (3.7) 0.236
Mortality, n (%) 3 (5.7) 1 (0.9) 0 (0) - 2 (2.2) 2 (1.5) -
Total, n (%) 11 (20.8) 20 (18.4) 16 (23.5) 0.706 18 (19.8) 29 (20.9) 0.842
Other Sick leave duration (weeks) 12 (2-52) 12 (1-28) 14 (2-48) 0.401 12 (1-48) 12 (3-52) 0.093

BMI = body mass index; CABG = coronary artery bypass graft; CAs = coronary arteries; CK = creatinine phosphokinase; cTnT = cardiac troponin T; CVI = cerebrovascular insult;
ECHO = echocardiography; MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; WC = waist circumference

Diabetologia Croatica 43-2, 2014 51

 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION

Table 2. Severity and prognosis of acute ST-elevation myocardial infarction according to WHtR (kg/m²) and WHR

WHtR WHtR WHtR WHR WHR

PARAMETERS <53/49 53/49-62/57 ≥63/58 p <0.90/0.85 ≥0.90/0.85 p
(n = 42) (n = 127) (n = 81) (n = 28) (n = 222)

Angina pectoris, n (%) 41 (97.6) 124 (97.6) 80 (98.8) 0.836 27 (96.4) 218 (98.2) 0.529
Clinical
Dyspnea, n (%) 15 (35.7) 36 (28.3) 24 (29.6) 0.662 10 (35.7) 65 (29.3) 0.484
presentation
Hospitalization (days) 8 (1-20) 9 (1-32) 9 (3-30) 0.366 9 (5-25) 9 (2-32) 0.193
Arrhythmias, n (%) 5 (11.9) 23 (18.1) 15 (18.5) 0.607 2 (7.1) 41 (18.5) 0.135
Conduction abnorm., n (%) 2 (4.8) 10 (7.9) 4 (4.9) 0.626 3 (10.7) 13 (5.9) 0.322
Heart failure, n (%) 9 (21.4) 26 (20.5) 29 (35.8) 0.038 9 (32.1) 55 (24.8) 0.400
Cardiogenic shock, n (%) 4 (9.5) 7 (5.5) 7 (8.6) 0.567 1 (3.6) 17 (7.7) 0.431

In-hospital Cardiac arrest, n (%) 5 (11.9) 17 (13.4) 14 (17.3) 0.649 2 (7.1) 34 (15.3) 0.246
complications Mechanical ventilation, n (%) 1 (2.4) 4 (3.1) 5 (6.2) 0.467 0 (0) 10 (4.5) 0.252
Reinfarction, n (%) 0 (0) 0 (0) 1 (1.2) - 0 (0) 1 (0.5) -
Re-PCI, n (%) 0 (0) 4 (3.1) 0 (0) - 0 (0) 4 (1.8) -
Mortality, n (%) 5 (11.9) 9 (7.1) 5 (6.2) 0.499 2 (7.1) 17 (7.7) 0.923
Total, n (%) 12 (28.6) 49 (38.6) 43 (53.1) 0.020 10 (35.7) 94 (42.3) 0.503
Max. cTnT (ng/mL) 3.7 (0.1-10) 3.7 (0-10) 2.6 (0-10) 0.061 2.1 (0-10) 3.2 (0-10) 0.071
Laboratory 2652 (107- 1983 (25- 1420 (85- 1324 (85- 1926 (25-
Max. CK (U/L) 0.118 0.122
15617) 13331) 14094) 11425) 15617)

Left ventricle ejection fraction

ECHO 50 (25-65) 50 (28-76) 55 (30-68) 0.691 50 (30-70) 50 (25-76) 0.944
(%)
Stenosed CAs 1.5 (1-3) 1 (1-4) 2 (1-4) 0.740 1.5 (1-4) 2 (1-4) 0.750
≥2 stenosed CAs, n (%) 21 (50.0) 62 (48.8) 45 (55.6) 0.629 14 (50) 114 (51.4) 0.893
Number of stents 1 (1-3) 1 (1-4) 1 (1-3) 0.432 1 (1-3) 1 (1-4) 0.119
Stent diameter (mm) 3 (2.8-4.0) 3.5 (2.5-4.0) 3.5 (2.3-4.0) 0.062 3 (2.8-4) 3.5 (2.3-4) 0.515
Coronary
angiography Stent length (mm) 20 (8-36) 20 (12-38) 20 (12-36) 0.291 20 (8-36) 20 (8-38) 0.905
Proximal/middle CAs
37 (88.1) 113 (89.7) 76 (93.8) 0.487 21 (75) 205 (92.8) 0.002
segment stenosis, n (%)
Distal CAs segments
15 (35.7) 51 (40.5) 31 (38.3) 0.850 15 (53.6) 82 (37.1) 0.092
stenosis, n (%)
Reinfarction, n (%) 0 (0) 1 (0.9) 1 (1.3) - 0 (0) 2 (1) -
Restenosis, n (%) 2 (5.4) 5 (4.3) 0 (0) - 1 (3.7) 6 (3) -
New stenosis, n (%) 2 (5.4) 3 (2.6) 2 (2.6) 0.659 2 (7.4) 5 (2.5) -
Cardiac rehosp., n (%) 3 (8.1) 22 (18.8) 12 (15.8) 0.303 2 (7.4) 35 (17.5) 0.183
MACE Non-cardiac rehosp., n (%) 1 (2.7) 6 (5.1) 2 (2.6) 0.626 1 (3.7) 8 (4) 0.941
CVI, n (%) 0 (0) 1 (0.9) 0 (0) - 0 (0) 1 (0.5) -
Urgent CABG, n (%) 0 (0) 4 (3.4) 2 (2.6) - 0 (0) 6 (3) -
Mortality, n (%) 0 (0) 3 (2.6) 1 (1.3) - 0 (0) 4 (2) -
Total, n (%) 5 (13.5) 28 (23.9) 14 (18.4) 0.340 7 (25.9) 40 (19.7) 0.451
Other Sick leave duration (weeks) 16 (2-24) 12 (1-52) 12 (3-40) 0.118 12 (10-26) 12 (1-52) 0.656

CABG = coronary artery bypass graft; CAs = coronary arteries; CK = creatinine phosphokinase; cTnT = cardiac troponin T; CVI = cerebrovascular insult; ECHO = echocardiography;
MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; WHR = waist-to-hip ratio; WHtR = waist-to-height ratio

52
 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION

paradoxical protective effect of central obesity, stenosis of proximal/middle CA segments, but without
whereas visceral fat may have an opposing effect and significant differences in other severity and in all
increase the risk of angiographic CAD. WC does not prognostic parameters.
add prognostic information for predicting six-month
Of the obesity indices, WHtR had the highest
mortality or myocardial reinfarction in patients with
positive correlation with CAD (40). This was the first
acute MI (35). Other authors have reported that WC is
study on the effect of WHtR on clinical severity and
not associated with an increased incidence of MACE
prognosis of acute STEMI. We found that WHtR
during 30-day follow up in patients with acute
≥63/58 increased the risk of heart failure and total in-
coronary syndrome (36). We found no significant
hospital complications. Considering the small number
differences in any of the parameters of severity and
of patients with normal WHR and WHtR values as the
prognosis between patients with normal and increased
main limitation of this study, investigation with a
WC.
higher number of patients should be performed to
The waist-to-hip ratio may indicate better confirm these results.
distribution of body fat (37). The presence of increased
In conclusion, WHR and for the first time used
WHR is associated with significant CA stenosis, but
WHtR are superior to BMI in predicting acute STEMI
not with the number of significantly stenosed CAs
severity, while WC has no influence on it. Obesity
(38). In acute STEMI, patients with WHR ≥0.90/0.85
indices have no impact on the prognosis (MACE,
more frequently have heart failure and WHR is an
SLD) of STEMI.
independent predictor of six-month mortality (39). In
our study, where a small number of patients with
normal WHR was found as expected, the presence of
increased WHR was associated with significant

Diabetologia Croatica 43-2, 2014 53

 M. Mornar Jelavić, Z. Babić, H. Pintarić, M. Mišigoj-Duraković / OBESITY AND ACUTE MYOCARDIAL INFARCTION
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Battler A, Hasdai D. Is increased body mass index 2001;74:315-321.
associated with a cardioprotective effect after ST-
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Talavera D, Díaz Guardiola P, Vega Piñero B, patients with ST-segment elevation acute
Monereo Megías S. Effect of abdominal obesity on myocardial infarction (from the Korean Acute
size of myocardial infarction. Endocrinol Nutr Myocardial Infarction Registry). Am J Cardiol
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56
1 Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic
Diseases, Merkur University Hospital, Zagreb, Croatia
2 School of Medicine, University of Zagreb, Zagreb, Croatia
GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
DECREASE SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN
OVERWEIGHT TYPE 2 DIABETIC PATIENTS
A. Ljubičić Pavić1, T. Bulum1, K. Blaslov1, J. Boras1, L. Duvnjak1,2
Key words: type 2 diabetes,
exenatide,
liraglutide,
blood pressure,
heart rate
SUMMARY
Glucagon-like peptide-1 (GLP-1) agonists are
increasingly used in the management of type 2
diabetes (T2DM), but their long-term cardiovascular
safety is not yet confirmed. In long-term clinical trials,
therapy with GLP-1 receptor agonists has been
associated with improvements in blood pressure but
also with increases in heart rate (HR). In the present
study, we assessed the effects of GLP-1 receptor
agonists exenatide and liraglutide on systolic blood
pressure (SBP), diastolic blood pressure (DBP) and
HR in overweight T2DM patients. A total of 85
overweight T2DM patients were included in the study
(43 on exenatide and 42 on liraglutide) and followed
up for 13 and 22 months. Treatment with exenatide
caused a significant decrease in SBP from 146±20 to
Corresponding author: Tomislav Bulum, MD, PhD, Vuk Vrhovac Clinic for
Diabetes, Endocrinology and Metabolic Diseases Merkur University
Hospital, Dugi dol 4a, HR-10000 Zagreb, Croatia
E-mail: tbulum@idb.hr
Diabetologia Croatica 43-2, 2014
Original Research Article
140±15 mm Hg (p=0.03), while DBP (from 88±10 to
85±7 mm Hg (p=0.1)) and HR (from 78±10 to 78±12
beats/min (p=0.9)) did not change significantly.
Treatment with liraglutide caused a significant
decrease in SBP from 145±20 to 135±18 mm Hg
(p=0.005) and DBP from 88±8 to 82±8 mm Hg
(p<0.001), while HR (from 78±14 to 73±8 beats/min
(p=0.2)) did not change significantly. The results of
our study suggest that therapy with GLP-1 receptor
agonists exenatide and liraglutide may significantly
reduce SBP and DBP by 6 to 10 mm Hg.
INTRODUCTION
Glucagon-like peptide-1 (GLP-1) receptor agonists
represent a novel class of therapies for type 2 diabetes
(T2DM) treatment with a potent blood glucose-
lowering action mediated via their ability to induce
insulin secretion and reduce glucagon secretion in a
glucose-dependent manner, but they also increase
pancreatic β cell mass, and suppress appetite and delay
in gastric emptying resulting in weight loss (1). These
medications primarily lower prandial and fasting
blood glucose levels by enhanced GLP-1 receptor
signaling. They lower blood glucose without fear from
hypoglycemia and preserve first-phase insulin
57
 A. Ljubičić Pavić, T. Bulum, K. Blaslov, J. Boras, L. Duvnjak / GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS DECREASE
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN OVERWEIGHT TYPE 2 DIABETIC PATIENTS
secretion. They are tailored to resist hydrolysis by
DPP-4 activity and to provide longer durability in the
circulation compared with native GLP-1 (1). Although
intestinal GLP-1 secretion is triggered by a diverse
variety of factors (metformin, interleukin-6, bile acids,
and so forth), the classical view is that GLP-1 is
secreted in the gut in response to nutrient ingestion as
part of the enteroinsular axis (2). They are also
efficient in reducing weight by slowing gastric
emptying rate and reducing appetite (3). GLP-1
receptor agonists are synthetic analogues of human
GLP-1 or exendin-4 based molecules. Exenatide,
originally derived from salivary glands of the Gila
monster with 53% homology with human GLP-1, was
the first GLP-1 receptor agonist introduced in clinical
practice. The once-daily human GLP-1 receptor
agonist liraglutide has 97% homology with human
GLP-1 with a single amino acid substitution extending
its half-life to up to 13 hours (4). In clinical trials,
exenatide and liraglutide significantly reduce HbA1c
up to 1.5% when used either as monotherapy or as an
add-on in combination with other oral hypoglycemic
agents and insulin (5). Favorable outcomes have also
been observed in systolic blood pressure (BP)
reduction, postprandial intestinal lipoprotein
metabolism, endothelial cell function, nonalcoholic
fatty liver disease, modulation of innate immune-
mediated inflammation and surrogate markers of renal
function (6, 7). However, small increases in heart rate
(HR) in long-term clinical trials with GLP-1 receptor
agonists have also been observed. As hypertension and
HR is an independent risk factor for premature death
in patients with T2DM, the potential extrapancreatic
effects, particularly within the heart and blood vessels,
of this drug class are of considerable clinical interest
(8). In the present study, we assessed the effects of
liraglutide and exenatide on systolic blood pressure
(SBP), diastolic blood pressure (DBP) and HR in
overweight T2DM patients.
SUBJECTS, MATERIALS AND METHODS
A total of 43 overweight T2DM patients on exenatide
were included and followed-up for 22 months (age
57±7 years, 22M/21F, body mass index (BMI) 38±5
kg/m2, weight 114±18 kg, HbA1c 8.6±1.2%, duration
58
of diabetes 11±6 years). Forty-two patients (18 male
and 24 female) on liraglutide were included in this
study too. They were followed up for 13 months (age
58±7 years, 18M/24F, BMI 38±5 kg/m2, weight
111±21 kg, HbA1c 8.1±0.9%, duration of diabetes
13±6 years). All subjects were studied in the morning
after an overnight fast. Basic anthropometric
measurements were performed on all study subjects,
including BMI and waist circumference (WC). Fasting
venous blood samples were collected in the morning
between 08:00 and 09:30 AM after an overnight fast
for determination of HbA1c. HbA1c was measured
spectrophotometrically by turbidimetric immuno-
inhibition (Olympus AU600, Beckman-Coulter,
USA). Results of HbA1c (%) are expressed in the
DCCT-equivalent. Blood pressure was measured twice
in the sitting position with a mercury sphy-
gmomanometer after a resting period of 10 minutes.
HR was determined using a standard 12-lead ECG
after a resting period of 10 minutes. Data on serum
creatinine levels, age, sex and race were used to
calculate the estimated glomerular filtration rate
(GFR) using the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) formula (9).
Exenatide was started as a 5-µg twice daily dose and
increased to 10 µg twice daily if needed in patients
with estimated GFR ≥60 mL/min-1/1.73 m2.
Liraglutide was started as a 0.6-mg once daily dose
and increased to up to 1.8 mg.
The study protocol complied with the Declaration of
Helsinki, as well as with local institutional guidelines,
and was approved by the local ethics committees. Data
are expressed as means ± SD for normally distributed
values, as median with range for non-normally
distributed values, and percentage. Differences
between groups were examined, depending on the
nature of the data, by parametric (t-test) or
nonparametric (Mann-Whitney) tests. Statistical
analysis was performed by statistical package
STATA/IC ver. 11.1.
 A. Ljubičić Pavić, T. Bulum, K. Blaslov, J. Boras, L. Duvnjak / GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS DECREASE
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN OVERWEIGHT TYPE 2 DIABETIC PATIENTS

RESULTS Treatment with liraglutide caused a significant

At the end of 22 months, 43 patients treated with
exenatide had significantly decreased HbA1c from
8.6±1.2 to 8.0±1.3% (p=0.01), BMI from 38±5 to
36±5 kg/m2 (p<0.001), weight from 114±18 to 106±18
kg (p<0.001), and WC from 119±12 to 115±11 cm
(p<0.001). The 22-month administration of exenatide
also caused a significant decrease in SBP from 146±20
to 140±15 mm Hg (p=0.03), while DBP (from 88±10
to 85±7 mm Hg (p=0.1)) and HR (from 78±10 to
78±12 beats/min (p=0.9)) did not change significantly
(Table 1).
decrease in BMI from 38±5 to 36±6 kg/m2 (p<0.001),
weight from 111±21 to 106±23 kg (p<0.001), and WC
from 120±14 to 114±15 cm (p=0.006), while HbA1c
(from 8.1±0.9 to 8.0±1.3% (p=0.1)) did not change
significantly. However, the 13-month administration
of liraglutide caused a significant decrease in SBP
from 145±20 to 135±18 mm Hg (p=0.005) and DBP
from 88±8 to 82±8 mm Hg (p<0.001), while HR (from
78±14 to 73±8 beats/min (p=0.2)) did not change
significantly (Table 2).

Table 1. Baseline and end-of-study characteristics of patients treated with exenatide

Baseline End of study p value

Age (years) 57±7
Gender (M/F) 22/21
Diabetes duration (years) 11±6
Waist circumference (cm) 119±12 115±11 <0.001
Body mass index (kg/m2) 38±5 36±5 <0.001
Weight (kg) 114± 18 106±18 <0.001
HbA1c (%) 8.6±1.2 8.0±1.3 0.01
Systolic BP (mm Hg) 146±20 140±15 0.03
Diastolic BP (mm Hg) 88±10 85±7 0.1
Heart rate (beats/min) 78±10 78±12 0.9
Estimated GFR (mL/min/1.73 m2) 89±18 90±17 0.2

BP, blood pressure; GFR, glomerular filtration rate

Table 2. Baseline and end-of-study characteristics of patients treated with liraglutide

Baseline End of study p value

Age (years) 58±7
Gender (M/F) 18/24
Diabetes duration (years) 13±6
Waist circumference (cm) 120±14 114±15 <0.001
Body mass index (kg/m2) 38±5 36±5 <0.001
Weight (kg) 111±21 106±23 <0.001
HbA1c (%) 8.1±0.9 8.0±1.3 0.1
Systolic BP (mm Hg) 145±20 135±18 0.005
Diastolic BP (mm Hg) 88±10 82±8 <0.001
Heart rate (beats/min) 78±14 73±8 0.2
Estimated GFR (mL/min/1.73 m2) 90±13 88±18 0.3

BP, blood pressure; GFR, glomerular filtration rate

Diabetologia Croatica 43-2, 2014 59

 A. Ljubičić Pavić, T. Bulum, K. Blaslov, J. Boras, L. Duvnjak / GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS DECREASE
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN OVERWEIGHT TYPE 2 DIABETIC PATIENTS
DISCUSSION
Incretin-based medications are a newer class of
diabetes therapies that are used worldwide for the
treatment of T2DM. They have excellent therapeutic
benefit in terms of HbA1c decline and weight
reduction as manifested by BMI decrease, which we
also confirmed in our study. Besides that, GLP-1
receptor agonists have other favorable effects on the
cardiovascular system and the endovasculature,
including BP reduction, which may be particularly
advantageous in the treatment of T2DM. The results of
our study suggest that therapy with the GLP-1 receptor
agonists liraglutide and exenatide may significantly
reduce SBP and DBP by 6 to 10 mm Hg and may offer
an alternative therapy for overweight T2DM.
Moreover, in our study, therapy with liraglutide and
exenatide was not associated with an increase in HR.
Consistent but modest SBP reductions ranging from
2.1 to 6.7 mm Hg for liraglutide were observed in the
Liraglutide Effect and Action in Diabetes (LEAD)
trials (10). Office SBP reductions are routinely
observed in clinical studies of 12-, 24- and 52-week
duration with GLP-1R agonist therapy. Detailed office
BP data from the LEAD studies demonstrated that
treatment with liraglutide (in doses of 1.2 mg and 1.8
mg) significantly reduced SBP early after introduction
(at 2 weeks, peaking at 4 weeks), preceding reductions
in body weight (11). A recent extensive systematic
meta-analysis and meta-regression by Katout et al.
(12) of GLP-1 receptor agonist in 12,469 patients
demonstrated that a greater reduction in SBP was
achieved with GLP-1 receptor agonists than with
active comparator therapy (2.97 vs. 1.47 mm Hg). As
expected, the SBP-lowering effect was associated with
a small increase in HR (0.26 vs. 2.33 beats/min). These
results are in keeping with another recent meta-
analysis by Robinson et al. (13), who demonstrated
that GLP-1 receptor agonist administration was
associated with a reduction in SBP by 1.79 mm Hg
(2.94 to 0.64 mm Hg) vs. placebo and 2.39 mm Hg
(3.35 to 1.42 mm Hg) vs. active control. A small
increase in HR of 1.86 beats/min was also observed.
60
A variety of mechanisms may contribute to the
antihypertensive effect(s) of GLP-1 receptor agonists.
The possible mechanisms include non-renal mediated
effects (weight loss, central inhibition of salt intake,
inhibition of intestinal salt absorption, neuronally
stimulated catecholaminergic activity, endothelial-
dependent vasodilatation) and renal-mediated effects
(natriuresis, renal Na+/H+ ion exchange activity, renal
hemodynamics (increased urinary flow/diuresis)) (14).
One unifying hypothesis that may partially account
for the antihypertensive effect(s) of GLP-1 receptor
agonists in humans is through the stimulation of
natriuresis. A small series of preclinical and clinical
studies have demonstrated that urinary sodium
excretion is triggered in response to short-term
infusion of GLP-17-36 amide and volume expansion
by hypertonic saline infusion. Gutzwiller et al. (15)
observed significant, dose-dependent increases in
urinary sodium excretion in healthy subjects, and in
obese, insulin-resistant subjects urinary sodium
excretion increased by 60% vs. placebo in response to
native GLP-1 infusion. This effect was observed in
parallel with increased chloride ion and calcium ion
filtration, suggesting a GLP-1-inhibitory effect at the
level of the proximal tubule. Additionally, urine
volume was also increased in response to GLP-17-36
amide infusion.
Skov et al. (16) have recently reported a reduction in
systemic levels of the potent vasoconstrictor
angiotensin II with acute GLP-1 infusion; however,
urinary angiotensinogen expression (a biomarker of
renal tissue RAAS activity) was unchanged in this
same study, suggesting that the effect of GLP-1 on
tissue intrarenal RAAS activity is unclear. More
recently, a novel link between BP reduction and
cardiac atrial natriuretic peptide (ANP) secretion in
response to GLP-1 receptor activation via liraglutide
was demonstrated in rodents rendered hypertensive by
angiotensin II infusion (17). Although previously
unrecognized, Kim et al. (17) importantly localized
GLP-1 receptor expression in the cardiac atrium but,
interestingly, not to the ventricles (where the majority
of the cardioprotective effect of GLP-1 receptor
agonists are thought to be targeted). In support to that
study, a small study involving Chinese patients with
 A. Ljubičić Pavić, T. Bulum, K. Blaslov, J. Boras, L. Duvnjak / GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS DECREASE
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN OVERWEIGHT TYPE 2 DIABETIC PATIENTS
T2DM and prehypertension showed significant
increases in ANP levels after 12 weeks of liraglutide
administration. At present, there are mixed data
supporting the relevance of a potential ANP-mediated
gut-heart-renal axis for GLP-1 receptor agonist-
dependent reductions in BP in humans.
In conclusion, a modest but significant lowering
effect on BP with GLP-1 receptor agonists has been
observed. A variety of mechanisms may contribute to
the antihypertensive effect(s) of GLP-1 receptor
agonists with natriuresis as the most important BP
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lowering mechanism. In our study, therapy with the
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significantly reduced SBP and DBP by 6 to 10 mm Hg,
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T2DM patients
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L. Treatment with a glucagon-like peptide-1
receptor agonist liraglutide decreases albuminuria
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RD, Zhong J, et al. Effect of GLP-1 mimetics on
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Diabetologia Croatica 43-2, 2014 63
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paper.
REVIEW AND PUBLICATION. The manuscripts are
reviewed anonymously. If the article is not accepted for
publication or certain alternations or additions are suggested, a
copy of the review, without the name of the reviewer, will be
sent to the author for final decision. The editorial board is not
obliged to publish articles in the order they are received.
Manuscripts are not returned and all printed supplements
become the property of the medical-scientific journal
Diabetologia Croatica.
Diabetologia Croatica 43-2, 2014 65