DOI: 10.1111/prd.
12283
REVIEW ARTICLE
Chronic hyperglycemia as a risk factor in implant therapy
Fawad Javed1 | Georgios E. Romanos1,2
1
Eastman Institute of Oral Health, University of Rochester, Rochester, NY, USA
2
Department of Oral Surgery and Implant Dentistry, Dental School, Johann Wolfgang Goethe University, Frankfurt, Germany
Correspondence
Georgios E. Romanos, Department of Periodontology, School of Dental Medicine, Stony Brook University, Stony Brook, New York, USA
Email: Georgios.Romanos@stonybrookmedicine.edu
1 |  D I A B E TE S M E LLIT U S A N D
PR E D I A B E TE S
Diabetes mellitus (commonly known as diabetes) is a group of meta‐
bolic disorders characterized by an absolute or partial insulin defi‐
ciency.1 The 4 basic types of diabetes are: (i) type 1 diabetes, which
occurs caused by the destruction of the pancreatic beta cells; (ii) type
2 diabetes, which accounts for at least 90% of cases of diabetes, and
occurs as a result of a progressive defect in insulin secretion; (iii) ges‐
tational diabetes, which may occur in the second or third trimester
of pregnancy; and (iv) diabetes occurring because of other causes
such as pancreatic anomalies (eg, pancreatic fibrosis) and drug‐ or
chemical‐induced diabetes, which may occur as a consequence of
organ transplantation.1 The diagnostic criteria of diabetes are sum‐
marized in Table 1.
Prediabetes is a state of abnormal glucose homeostasis charac‐
terized by the presence of impaired fasting glucose, impaired glu‐
cose tolerance, or both. Prediabetes designations, that is, impaired
fasting glucose and impaired glucose tolerance, have been defined
as fasting glucose levels of 100‐125 mg/dL and postglucose chal‐
1
lenge levels of 140‐199 mg/dL, respectively. According to a supple‐
ment published by the American Diabetes Association,1 individuals
with prediabetes are at an increased risk of underdeveloped diabe‐
tes. The diagnostic criteria of prediabetes are summarized in Table 2.
2 |  G LO BA L E PI D E M I O LO G Y O F
D I A B E TE S —A B R I E F OV E RV I E W
In 2000, the global prevalence of diabetes for all age groups was es‐
timated to be 2.8%3; however, it has been predicted that by 2030 the
3
prevalence of adult diabetes will rise to 4.4%. The same study pre‐
dicts that in 2030, India will have the highest number of patients with
diabetes (79.4 million) followed by China and the USA (42.3 million
Periodontology 2000. 2019;81:57–63. wileyonlinelibrary.com/journal/prd   © 2019 John Wiley & Sons A/S. |  57
and 30.3 million, respectively).3 In Bangladesh and Pakistan, there
were approximately 3 and 5 million patients with diabetes in 2000,
respectively; and these numbers are expected to rise to nearly 11
and 14 million by 2030, respectively. It was also estimated that in
2030, the number of patients with diabetes aged > 64 years will be
> 82 million in underdeveloped countries, and > 48 million in devel‐
oped countries.3
3 | E FFEC T O F D I A B E TE S O N WO U N D
H E A LI N G
A cascade of molecular events is associated with wound heal‐
ing because the affected area experiences intense metabolism.
A series of changes in wound healing at the molecular level has
been found in patients with diabetes that may compromise heal‐
ing and potentially cause ulcer formation. In a study on pigs with
and without streptozotocin‐induced diabetes, wound contraction
was analyzed, and biopsies were obtained for measurement of re‐
epithelialization.4 The wound fluid was also analyzed for insulin‐
like growth factor‐1 and transforming growth factor‐beta in both
groups. The results showed that there was a significant reduction
in both re‐epithelialization and insulin‐like growth factor‐1, and
also that transforming growth factor‐beta levels were significantly
lower in the wound fluid among pigs without streptozotocin‐in‐
duced diabetes.4 In summary, the study showed that wound
healing was significantly delayed in pigs without streptozotocin‐
induced diabetes.4 Similarly, in a recent histomorphometric study,
Brizeno et al5 investigated the healing of induced oral mucosal ul‐
cerations in rats with and without alloxan‐induced diabetes. The
results showed that there was a delay in wound closure of oral
mucosal ulcerations in rats with diabetes compared with controls
(normoglycemic rats). 5 Histomorphometric results showed a sig‐
nificantly increased expression of polymorphonuclear leukocytes
Published by John Wiley & Sons Ltd
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58       JAVED and ROMANOS
Diagnostic parameter Criteria
Hemoglobin A1c ≥6.5%
Fasting plasma glucose level ≥126 mg/dL (7 mmol/L)
2 h plasma glucose ≥200 mg/dL (11.1 mmol/L), during a 75 g
glucose load
Random plasma glucose ≥200 mg/dL (11.1 mmol/L), with symptoms of
hyperglycemia or hyperglycemic crisis
in the lesions of rats with alloxan‐induced diabetes compared with
controls, and angiogenesis in the wound area was significantly re‐
duced among rats with alloxan‐induced diabetes compared with
controls. Furthermore, this study also showed that diabetes re‐
duced collagen deposition and the number of fibroblasts in the
wound area, and there was an increased expression of proin‐
flammatory cytokines (interleukin‐1beta and tumor necrosis fac‐
tor‐alpha) in the oral epithelium of rats with diabetes compared
with controls. 5 Impaired wound healing in patients with diabetes
has also been associated with inhibition of production of stromal
cell‐derived factor‐1alpha by several tissues including bone mar‐
6,7
row, brain, heart, spleen, and gingiva. Other factors associated
with delayed wound healing among patients with diabetes en‐
compass malnutrition, neuropathy, and vascular damage. 8 From a
clinical perspective, impaired wound healing and limb amputations
for nontraumatic wounds are common complications observed
among patients with diabetes compared with systemically healthy
individuals.9
4 |  D E NTA L I M PL A NT S I N M E D I C A LLY
CO M PRO M I S E D PATI E NT S
Dental implants are a modern substitute for conventional fixed
and removable dental prostheses (bridges and dentures, respec‐
tively) and are used for the oral rehabilitation of partially and/or
completely edentulous individuals. With advancements in clinical
dentistry and research, dental implant therapy is not restricted to
systemically healthy individuals, and patients with systemic dis‐
eases such as diabetes mellitus are also suitable candidates for
dental rehabilitation using dental implants.10,11 In a recent clini‐
12
cal retrospective cohort study, the influence of systemic disease
on the outcome of dental implant therapy was investigated. In
this study, 528 dental implants were placed in 93 patients with
systemic diseases, namely, cardiovascular diseases, diabetes, os‐
teoporosis, and hypothyroidism, and also in patients with more
than one of these diseases. Implant failure rates in these patients
were compared with 475 dental implants that were placed in 111
systemically healthy individuals. Implant failure rates were simi‐
lar among patients with systemic diseases (11.8%) and controls
(16.2%).12 The study outcomes emphasized that medically com‐
promised patients can undergo dental implant therapy and can ex‐
hibit implant survival rates similar to those in systemically healthy
TA B L E 1   Diagnostic criteria of
diabetes mellitus set by the American
Diabetes Association (modified from the
criteria set by the American Diabetes
Association1,2)
individuals.12 These results suggest that systemic illness is not a
contraindication for dental implant therapy.
5 | I M PAC T O F C H RO N I C
H Y PE RG LYC E M I A O N
OS S EO I NTEG R ATI O N — LE S S O N S FRO M
E X PE R I M E NTA L S T U D I E S
Integrin alpha‐5 beta‐1 and fibronectin are proteins found in the
extracellular matrix that have been reported to enhance the at‐
tachment of osteoblasts on implant surfaces.13,14 Results from a
study on Zucker diabetic fatty rats showed that chronic hypergly‐
cemia interferes with the osseointegration of implants by defer‐
ring expression of fibronectin and integrin alpha‐5 beta‐1.15 Results
from another study on rats with streptozotocin‐induced diabetes
showed that chronic hyperglycemia impairs bone density around
osseointegrated implants placed in rat tibiae.16 Quintero et al17
tested the hypothesis that advanced glycation end products, which
accumulate in body tissues with advancing age and under hyper‐
glycemic conditions, inhibit osseointegration and compromise the
biomechanical properties at the bone‐implant interface. In this
study,17 titanium implants (1 × 3 mm) were placed in the healed
sockets of 16 rats, consisting of 1 group of 8 rats injected 3 times
per week for 1 month with advanced glycation end products, and
another group of 8 rats injected with vehicle to act as control.
Advanced glycation end products were injected for an additional
14 or 28 days until euthanasia. Radiographic images were used to
calculate bone‐to‐implant contact ratios, and tissue samples were
collected for immunohistochemistry with antibodies to advanced
glycation end products and the bone turnover‐marker protein
matrix metalloproteinase1. The results showed that the controls
TA B L E 2   Diagnostic criteria of prediabetes set by the American
Diabetes Association (modified from the criteria set by the
American Diabetes Association1,2)
Diagnostic parameter Criteria
Hemoglobin A1c ≥5.7% to 6.4%
Fasting plasma glucose level ≥126 mg/dL to
<126 mg/dL
2 h plasma glucose ≥140 mg/dL to
<200 mg/dL
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      59

TA B L E 3   Outcomes of experimental studies that assessed the impact of induced diabetes on osseointegration

Reference Test group Control group Investigative parameter Outcome

19
Hasegawa et al Rats with STZ‐in‐ Rats without BIC BIC was significantly higher in the control
duced diabetes diabetes group compared with the test group
Kopman et al20 Rats with STZ‐in‐ Rats without BIC BIC was significantly higher in the control
duced diabetes diabetes group compared with the test group
Kwon et al21 Rats with STZ‐in‐ Rats without BIC BIC was significantly higher in the control
duced diabetes diabetes group compared with the test group
Nevins et al23 Rats with STZ‐in‐ Rats without BIC BIC was significantly higher in the control
duced diabetes diabetes group compared with the test group
Shyng et al24 Rats with STZ‐in‐ Rats without Mineral apposition Mineral apposition was significantly higher
duced diabetes diabetes in the control group compared with the test
group
Siqueira et al53 Rats with alloxan‐in‐ Rats without Bone area and BIC BIC and bone area were significantly higher
duced diabetes diabetes in the control group compared with the test
group
Wang et al54 Rats with fat diet‐ Rats without BIC, osteoid and osteo‐ BIC, osteoid and osteogenic volume were
induced diabetes diabetes genic volume significantly higher in the control group com‐
pared with the test group

BIC, bone‐to‐implant contact; STZ, streptozotocin.

showed significantly higher bone‐to‐implant contact at both 14 and

28 days compared with the groups treated with advanced glycation
end products.17 These results indicate that chronic hyperglycemia
contributes to a slower rate of osseointegration, which, if left un‐
treated, may jeopardize implant stability. According to Catalfamo
et al,18 persistent hyperglycemia plays a role in abnormal differen‐
tiation of osteoclasts, thereby making bone tissue more susceptible
to resorption. Table 3 summarizes the outcomes of experimental
studies19-24 that assessed the impact of induced diabetes on os‐
seointegration (Figure 1).

6 | I M PAC T O F C H RO N I C
H Y PE RG LYC E M I A O N TH E S U CC E S S
A N D S U RV I VA L O F D E NTA L I M PL A NT S —
LE S S O N S FRO M C LI N I C A L S T U D I E S
Clinical evidence25-27 from indexed literature has shown that chronic
hyperglycemia in patients with diabetes is associated with peri‐im‐
plant soft tissue inflammation, crestal bone loss, and even implant
failure. In a 2‐year follow‐up study, Aguilar‐Salvatierra et al25 com‐
pared implant survival and primary stability parameters among
patients with diabetes with varying levels of hemoglobin A1c. The
results showed that peri‐implant bleeding on probing, crestal bone
loss, and probing depth showed a tendency to increase in proportion
with rising hemoglobin A1c levels. The study concluded that dental
implants are a suitable treatment option for patients with diabetes
provided their glycemic levels are at least moderately well con‐
25
trolled. Similarly, clinical results from a research group in Spain also
reported that poorly controlled hemoglobin A1c levels causes are
associated with both higher bleeding on probing and crestal bone
loss around dental implants. 26
F I G U R E 1   A schematic presentation of the effects of chronic
hyperglycemia on cells and tissues
Interestingly, in a recent clinical study, Eskow and Oates10 re‐
ported that patients with poorly controlled (hemoglobin A1c levels
of 8% to 12%) type 2 diabetes can demonstrate high implant survival
rates (96.6%). Similarly, results from another study showed that pa‐
tients with poorly controlled type 2 diabetes (with hemoglobin A1c
levels as high as 13.3%) demonstrated implant survival rates of up to
100%. In another 12 month follow‐up clinical trial, Ghiraldini et al28
investigated the influence of glycemic control among patients with
type 2 diabetes on the implant stability quotient. The results showed
no statistically significant difference in implant stability quotient val‐
ues despite differences in glycemic control among patients with type
2 diabetes.28
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60       JAVED and ROMANOS
7 |  I M PAC T O F G LYC E M I C CO NTRO L O N
TH E S U CC E S S A N D S U RV I VA L O F D E NTA L
I M PL A NT S — LE S S O N S FRO M C LI N I C A L
STUDIES
Although research12 has shown that dental implants can remain
functionally stable in patients with diabetes, such outcomes should
be interpreted with caution as these studies imposed strict eligibility
criteria for inclusion. In the Manor et al study,12 patients with poorly
controlled medical conditions, such as poorly controlled diabetes or
hypertension, were excluded. Moreover, patients on intravenous bi‐
sphosphonate therapy were also not included. Similarly, in the Dogan
30
et al study, there was no statistically significant difference in the
levels of proinflammatory cytokines (interleukin‐1beta and tumor
necrosis factor‐alpha) in the gingival crevicular fluid and peri‐implant
sulcular fluid of patients with or without type 2 diabetes. This study
also reported that at follow‐up evaluation there was no statistically
significant difference in peri‐implant bone levels in patients with or
without type 2 diabetes. In another study, 29 crestal bone levels were
compared for immediate and delayed loaded dental implants placed
in patients with and without type 2 diabetes. The results showed no
statistically significant difference in peri‐implant bleeding on prob‐
ing, probing depth, and crestal bone loss for immediate and delayed
loaded implants in either group. It is important to note that in the
29
study by Al Amri et al, all of the patients had well‐controlled type 2
diabetes and were approximately 50 years old. Moreover, the maxi‐
30
mum follow‐up periods in the studies by Dogan et al and Al Amri
et al29 were 7 and 24 months, respectively. It is hypothesized that
crestal bone loss around dental implants placed in patients with type
2 diabetes would have been significantly higher compared with con‐
trols if the studies by Al‐Amri et al29 and Dogan et al30 each had a
longer follow‐up period (≥ 5 years). Because crestal bone loss around
teeth increases with advancing age,31 it is speculated that crestal
bone loss around dental implants placed in older patients (aged ≥
75  years) is significantly higher than in younger patients (aged ≤
50 years). There is also a possibility that chronic hyperglycemia in
older patients jeopardizes peri‐implant inflammatory parameters
(such as bleeding on probing, probing depth, and crestal bone loss)
to a significantly greater extent compared with younger patients
with chronic hyperglycemia. Further studies are warranted to test
these hypotheses. In a recent systematic review and meta‐analysis,
32
Moraschini et al investigated the hypothesis that the implant sur‐
vival rates in patients with type 1 and type 2 diabetes and systemi‐
cally healthy individuals are comparable; 14 studies were included
in this systematic review and meta‐analysis,32 and results suggested
that implant survival does not differ in patients with or without dia‐
betes. Moreover, the results showed no statistically significant dif‐
ference in the number of implant failures among patients with type 1
and 2 diabetes.32 The authors of the current paper critically assessed
32
the studies included in this systematic review and meta‐analysis,
and the most salient feature was that all of the patients participat‐
ing in the studies had well‐controlled diabetes. Another potential
source of confusion and bias is that none of the studies included in
this systematic review and meta‐analysis32 monitored the glycemic
levels of the participants throughout the study period. Nevertheless,
we applaud the fact that dental implants placed in patients with and
without diabetes can have high survival rates; however, the role of
stringent glycemic control in this regard cannot be overlooked.33,34
8 | S U CC E S S A N D S U RV I VA L O F D E NTA L
I M PL A NT A M O N G PATI E NT S W ITH
PR E D I A B E TE S
Studies35-39 have shown that prediabetes is a significant risk fac‐
tor for periodontal soft tissue inflammation and crestal bone loss
around teeth; however, to date, there have only been 3 studies40-42
in literature that have assessed peri‐implant inflammatory status
among patients with prediabetes. Abduljabbar et al41 assessed peri‐
implant plaque index, bleeding on probing, probing depth, and cr‐
estal bone loss among individuals without diabetes and patients with
prediabetes and type 2 diabetes. The results showed that peri‐im‐
plant plaque index, bleeding on probing, probing depth, and crestal
bone loss were significantly higher among patients with prediabetes
and type 2 diabetes compared with controls; however, there was no
difference in these parameters among patients with prediabetes and
type 2 diabetes.41 On the contrary, in the study by Al Amri et al,42
survival rates of dental implants placed in patients with and without
prediabetes were 100%. A major limitation of these studies 41,42 was
the relatively short duration of the follow‐up periods: in the studies
conducted by Al Amri et al42 and Abduljabbar et al,41 the maximum
follow‐up periods were 12 and approximately 24 months, respec‐
tively. Further long‐term follow‐up studies are therefore needed to
assess the impact of prediabetes on the success and survival of den‐
tal implants.
9 | B LO O D G LU COS E LE V E L—TO CO NTRO L
O R N OT TO CO NTRO L? TH AT I S TH E
QU E S TI O N
Some clinical studies10,11 have shown that dental implants placed
in patients with poorly controlled diabetes can exhibit high survival
rates; however, the authors of the current paper perceive that the
level or quality of evidence provided in these studies10,11 is insuffi‐
cient to provide a factual platform to justify the placement of dental
implants in patients with poorly controlled diabetes. Results of the
Oates et al study11 should be interpreted with caution because its
authors used certain stringent protocols such as a 7‐day postopera‐
tive antibiotic cover, 2 weeks of chlorhexidine oral rinses, and delay‐
ing implant loading for 4 months (instead of 2 months, which is the
usual protocol). These factors may have contributed to achieving the
desired conclusion, which is that elevated hemoglobin A1c levels are
not associated with altered implant survival after 12 months of load‐
ing in patients with type 2 diabetes. Moreover, in this study,11 the
conclusion was based on implant stability (an assessment of implant
JAVED and ROMANOS
stability quotient) rather than more critical parameters such as long‐
term implant success and survival rates. From a medical perspective,
chronic hyperglycemia has been shown to have adverse effects on
the outcomes of carotid artery stenting,43 and is also a potential risk
factor for prosthetic joint infections in total hip and knee arthro‐
44
plasty. Furthermore, it is also well known that poor glycemic sta‐
tus in patients with diabetes can expose these individuals to serious
medical conditions including heart failure, renal failure, pancreatic
cancer, intracerebral hemorrhage, hepatocellular carcinoma, and
45-50
gastrointestinal malignancies. Taking all the above into consid‐
eration, when poorly controlled diabetes has been shown to be as‐
sociated with failures of cardiac stents and prosthetic joints, and can
expose humans to life‐threatening medical disorders, then is there a
logical and scientific justification to place dental implants in patients
with poorly controlled diabetes? In this regard, we strongly empha‐
size that glycemic control/maintenance plays an essential role in the
33
overall success and survival of dental implants, and also helps to
improve the quality of life for patients with diabetes.51,52
10  | R ECO M M E N DATI O N S FO R O R A L
H E A LTH C A R E PROV I D E R S TR E ATI N G
PATI E NT S W ITH D I A B E TE S (R EG A R D LE S S
O F W H E TH E R TH E PATI E NT H A S
U N D E RG O N E D E NTA L I M PL A NT TH E R A PY
O R N OT )
There follows a list of recommendations that may help to improve
the oral health and peri‐implant status of patients with diabetes. We
believe that these suggestions may also have a positive impact on
the overall health status of people living with diabetes:
• comprehensive health history: a detailed record of a patient's
medical health history should be obtained at the initial examina‐
tion and revised/updated regularly. For patients with a previous
history of diabetes, additional details (such as duration of the dis‐
order, family history of diabetes, the type of treatment used for
glycemic control, and current glycemic status [including, ideally,
hemoglobin A1c level]) should be recorded. In addition, other fac‐
tors besides poorly controlled diabetes that may jeopardize the
outcomes of future oral surgical interventions (such as tobacco
smoking) should also be recorded.
• decision‐making for implant therapy: based on the most up‐to‐
date evidence from basic scientific and clinical research,19 it is ad‐
vised that dental implant therapy should be postponed in patients
with poorly controlled diabetes, and should only be performed
when glycemic control is achieved.
• patient education: routine community‐based educational pro‐
grams should be performed to educate the general public about
the hazardous effects of poor glycemic control and the benefits
of glycemic maintenance on health, including oral health. In ad‐
dition, oral healthcare providers should also educate their pa‐
tients accordingly, particularly those with a previous diagnosis
|
      61
of diabetes. The importance of routine medical and dental ex‐
aminations should also be emphasized, because these may be
helpful in the early diagnosis and treatment of oral and sys‐
temic diseases such as diabetes and periodontal/peri‐implant
diseases, respectively.
• healthcare provider education: healthcare providers should be
encouraged to keep themselves up‐to‐date with the most recent
advancements in the management of oral and systemic diseases
through scientific literature, seminars/symposia, conferences,
and workshops.
11 | CO N C LU S I O N
Dental implants can osseointegrate and remain functionally stable in
patients with diabetes. The significance of optimal glycemic control
is emphasized.
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How to cite this article: Javed F, Romanos GE. Chronic
hyperglycemia as a risk factor in implant therapy. Periodontol
2000. 2019;81:57–63. https​://doi.org/10.1111/prd.12283​