Effect of Intensive Glycemic Control on Platelet Reactivity in Patients with Long-standing Uncontrolled Diabetes Joelle Singer, Adaya Weissler Snir, Dorit Leshem-Lev, Merav Rigler, Ran Kornowski, Eli I. Lev PII: DOI: Reference:
S0049-3848(14)00275-8 doi: 10.1016/j.thromres.2014.05.010 TR 5520
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
21 January 2014 3 May 2014 7 May 2014
Please cite this article as: Singer Joelle, Snir Adaya Weissler, Leshem-Lev Dorit, Rigler Merav, Kornowski Ran, Lev Eli I., Effect of Intensive Glycemic Control on Platelet Reactivity in Patients with Long-standing Uncontrolled Diabetes, Thrombosis Research (2014), doi: 10.1016/j.thromres.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Effect of Intensive Glycemic Control on Platelet Reactivity in Patients with Long-standing Uncontrolled Diabetes
Endocrinology Department, Rabin Medical Center, Petah-Tikva, Israel
b
Cardiology Department, Rabin Medical Center, Petah-Tikva, and the Sackler Faculty
of Medicine, Tel-Aviv University, Israel
The Felsenstein Medical Research Institute, Petah-Tikva, Israel
PT
Total word count: 3,637
ED
MA
c
NU
a
SC RI
Riglera, Ran Kornowski, MDb,c, Eli I. Lev, MDb,c, *
PT
Joelle Singer, MDa, †, Adaya Weissler Snirb, †,, MD, Dorit Leshem-Lev, PhDc, Merav
AC
CE
Corresponding author: Dr. Eli Lev, Department of Cardiology, Rabin Medical Center, Petah-Tikva, Tel-Aviv University, Israel. Tel: 972-3-9372251; fax: 972-3-9231016; Email: [email protected] , [email protected] † Drs. Singer and Weissler Snir contributed equally to this article.
ACCEPTED MANUSCRIPT Background: It has been previously shown that platelets of patients with diabetes are more reactive and less responsive to anti-platelet drugs compared with platelets from
PT
subjects without diabetes. Studies examining the effect of glycemic control on platelet reactivity have yielded conflicting data. Thus, in this study, we sought to explore the
SC RI
effect of tight glycemic control on platelet reactivity in patients with long standing uncontrolled diabetes.
Methods: The study included 30 patients with long-standing treated diabetes and a
NU
baseline HbA1c level of ≥ 8.5%. All patients were treated with aspirin and statins.
MA
Patients were tested at baseline and after 3 months of intensive glycemic and metabolic control. The treatment goal was to achieve a HbA1c level of ≤7%. Platelet
ED
reactivity was assessed by light transmission aggregation in response to 5 and 10 µM ADP and to 0.5 mg/ml arachidonic acid (AA). Additonally, platelet activation was
PT
assessed by plasma levels of soluble P-selectin using an enzyme-linked immunosorbent assay.
CE
Results: The mean duration of diabetes from the time of diagnosis was
AC
20.46±9.31years. Baseline HbA1c was 9.4±0.8%. Following the intensive glycemic control period, the HbA1C level decreased to 8.1±0.8% (P 7% and did not consider diabetes duration as a significant factor when examining the relation between glycemic control and platelet reactivity.
ACCEPTED MANUSCRIPT To our knowledge, this is the first study to assess the effect of tight glycemic control on platelet reactivity in stable patients with severely uncontrolled longstanding DM.
PT
A previous study by Vivas et al has shown no reduction in platelet reactivity after long term (12 months) optimized glucose control with insulin in patients presenting
SC RI
with an ACS and hyperglycemia [31]. The same group however has found a reduction in platelet reactivity after intensive glucose control during the hospitalization for ACS in patients with elevated HbA1c levels > 6.5% [30]. Another study by Mangiacapra
NU
et al on patients with type 2 DM undergoing elective PCI has found that glycemic
MA
control did not appear to influence platelet reactivity following a loading dose of 600 mg of clopidogrel and aspirin treatment [32]. Similarly, Gaborit et al have found no
ED
correlation between platelet reactivity and glycemic control parameters in diabetic patients on clopidogrel. Furthermore, in 15 poorly controlled type 2 diabetic patients,
PT
optimal glycemic control for one week did not modify platelet test results [33]. In contrast, Demirtunc et al have found a positive association between 3 months of
CE
improved glycemic control and mean platelet volume in type 2 patients with baseline
AC
HbA1c>7%. They however did not perform platelet aggregation tests. Notably the mean duration of diabetes was shorter than in the current study (5.9±4.8 years) [36]. Aoki et al have demonstrated significantly higher platelet-dependent thrombin generation in patients with poorly controlled non-insulin-dependent DM without complications (HbA1c > 9%) than in well controlled diabetic patients without complications (Hb A1c < 9 %) [16]. Although high platelet reactivity in patients with diabetes has been attributed among other factor to hyperglycemia [20,21] we did not detect a significant reduction in ADP-induced platelet aggregation (5 and 10 µM), arachidonic acid aggregation test or in soluble P-selectin levels after the achievement of better glycemic control in patients with longstanding poorly controlled DM.
ACCEPTED MANUSCRIPT One possible explanation is that hyperglycemia plays only a minor role in platelet reactivity in patients who have had high levels of glycemia for many years, and that
PT
other factors associated with DM contribute more to platelet reactivity, such as inflammation, insulin resistance and obesity. Notably, metabolic characteristics
SC RI
including obesity did not differ between the baseline and the post-glycemic control period. Another explanation might be that although there was a significant reduction in HbA1c level, most patients did not achieve a target HbA1c of 7% or less and hence
NU
optimal glycemic control was not achieved in the majority of patients.
MA
It is noteworthy that the baseline platelet aggregation values and P-selectin levels observed in the current study were similar to values of control patients taking aspirin
ED
from a previous study performed by our lab [37].
PT
Our study has several limitations. The main limitation is that the original target HbA1C of 7% was not met in most patients. However, all patients achieved a
CE
significant reduction in HbA1C level (a mean decrease of 1.4%), which was not
AC
associated with a reduction in platelet reactivity. Another limitation is that the regimen aimed at achieving glycemic control differed between the patients and consisted of various medications with or without insulin, as well as changes in diet, physical activity and glucose monitoring. Insulin, for instance, may have direct effects on the inflammatory system [35], which in turn affects platelet reactivity. Finally, the sample size was relatively small. In conclusion, this study showed that intensive glycemic control in patients with longstanding uncontrolled diabetes does not seem to result in a reduction in platelet reactivity. Further investigation is required to validate these findings, and to seek
ACCEPTED MANUSCRIPT alternative strategies to manage platelet hyper-reactivity in patients with type 2
AC
CE
PT
ED
MA
NU
SC RI
PT
diabetes.
ACCEPTED MANUSCRIPT Table 1. Baseline Characteristics
59.9±13.3
Women
7 (23.3%)
BMI (kg/m2)
32.21±8.04
Hypertension
21 (70%)
Dyslipidemia†
28 (93.3%)
Current smoking
4 (13.3%)
NU
SC RI
Age (years)
14 (46.6%)
Prior MI
21 (70%)
MA
Prior PCI
7 (23.3%)
Prior CABG
3 (10%)
Baseline Medications
PT
Aspirin
AC
CE
Statins
Beta blockers
ED
Prior stroke
Clopidogrel
PT
Demographic characteristics
ACE inhibitors / ARB
30 (100%) 30 (100%) 6 (20%) 22 (73.3%) 27 (90%)
† Diagnosis previously made by physician or receiving lipid-lowering therapy BMI = body mass index; MI = myocardial infarction; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; ACE = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers
ACCEPTED MANUSCRIPT Table 2. Clinical characteristics
Type I DM
6 (20%)
Disease
20.5±9.3
PT
Clinical Characteristics
12 (40%)
Retinopathy*
13 (43.3%)
Nephropathy*
24 (80%)
Peripheral
5 (16.6%)
NU
Neuropathy*
SC RI
duration (years)
vascular disease
23 (76.6%)
MA
Coronary artery disease†
Baseline 92.8±14
Medications
Baseline
3-4 months
Sulfonylurea
9 (30%)
6 (20%)
PT
ED
Weight (kg)
Post 93.1±14
22 (73.3%)
23 (76.6%)
1 (3.3%)
0
2 (6.6%)
2 (6.6%)
Insulin (any)
22 (73.3%)
26 (86.6%)
Insulin pump
2 (5.7%)
2 (5.7%)
3.8±1
3.7±1
80.9±45
78.6±41
49% / 51%
54% / 46%
Glitazones
CE
Metformin
AC
GLP-1 agonists
Insulin injections/day** Total daily insulin (units) Proportion of short / long acting insulin
* diagnosis made by treating physician; † history of myocardial infarction or coronary angiography demonstrating significant stenosis; ** in patients treated with insulin injections; BMI = body mass index; GLP-1 = glucagon-like peptide-1
ACCEPTED MANUSCRIPT Table 3. Laboratory parameters Laboratory Parameter
Baseline
After Intensive
PT
Glycemic Control 9.4±0.8 *
8.1±0.8 *
Hemoglobin (g/dL)
13.7±1.4
13.3±1.3
Platelets (103/mm3)
248±62
WBC (103/mm3)
7.5±2.2
Creatinine (mg/dL)
0.9±0.3
SC RI
HbA1c (%)
245±64 7.6±2.6
NU
0.9±0.3
73.5±23.2
80.1±25.2
HDL-c (mg/dL)
46.0±13.0
47.7±13.5
Triglycerides (mg/dL)
190±166 †
MA
LDL-c (mg/dL)
146±95 †
* P
S0049-3848(14)00275-8 doi: 10.1016/j.thromres.2014.05.010 TR 5520
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
21 January 2014 3 May 2014 7 May 2014
Please cite this article as: Singer Joelle, Snir Adaya Weissler, Leshem-Lev Dorit, Rigler Merav, Kornowski Ran, Lev Eli I., Effect of Intensive Glycemic Control on Platelet Reactivity in Patients with Long-standing Uncontrolled Diabetes, Thrombosis Research (2014), doi: 10.1016/j.thromres.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Effect of Intensive Glycemic Control on Platelet Reactivity in Patients with Long-standing Uncontrolled Diabetes
Endocrinology Department, Rabin Medical Center, Petah-Tikva, Israel
b
Cardiology Department, Rabin Medical Center, Petah-Tikva, and the Sackler Faculty
of Medicine, Tel-Aviv University, Israel
The Felsenstein Medical Research Institute, Petah-Tikva, Israel
PT
Total word count: 3,637
ED
MA
c
NU
a
SC RI
Riglera, Ran Kornowski, MDb,c, Eli I. Lev, MDb,c, *
PT
Joelle Singer, MDa, †, Adaya Weissler Snirb, †,, MD, Dorit Leshem-Lev, PhDc, Merav
AC
CE
Corresponding author: Dr. Eli Lev, Department of Cardiology, Rabin Medical Center, Petah-Tikva, Tel-Aviv University, Israel. Tel: 972-3-9372251; fax: 972-3-9231016; Email: [email protected] , [email protected] † Drs. Singer and Weissler Snir contributed equally to this article.
ACCEPTED MANUSCRIPT Background: It has been previously shown that platelets of patients with diabetes are more reactive and less responsive to anti-platelet drugs compared with platelets from
PT
subjects without diabetes. Studies examining the effect of glycemic control on platelet reactivity have yielded conflicting data. Thus, in this study, we sought to explore the
SC RI
effect of tight glycemic control on platelet reactivity in patients with long standing uncontrolled diabetes.
Methods: The study included 30 patients with long-standing treated diabetes and a
NU
baseline HbA1c level of ≥ 8.5%. All patients were treated with aspirin and statins.
MA
Patients were tested at baseline and after 3 months of intensive glycemic and metabolic control. The treatment goal was to achieve a HbA1c level of ≤7%. Platelet
ED
reactivity was assessed by light transmission aggregation in response to 5 and 10 µM ADP and to 0.5 mg/ml arachidonic acid (AA). Additonally, platelet activation was
PT
assessed by plasma levels of soluble P-selectin using an enzyme-linked immunosorbent assay.
CE
Results: The mean duration of diabetes from the time of diagnosis was
AC
20.46±9.31years. Baseline HbA1c was 9.4±0.8%. Following the intensive glycemic control period, the HbA1C level decreased to 8.1±0.8% (P 7% and did not consider diabetes duration as a significant factor when examining the relation between glycemic control and platelet reactivity.
ACCEPTED MANUSCRIPT To our knowledge, this is the first study to assess the effect of tight glycemic control on platelet reactivity in stable patients with severely uncontrolled longstanding DM.
PT
A previous study by Vivas et al has shown no reduction in platelet reactivity after long term (12 months) optimized glucose control with insulin in patients presenting
SC RI
with an ACS and hyperglycemia [31]. The same group however has found a reduction in platelet reactivity after intensive glucose control during the hospitalization for ACS in patients with elevated HbA1c levels > 6.5% [30]. Another study by Mangiacapra
NU
et al on patients with type 2 DM undergoing elective PCI has found that glycemic
MA
control did not appear to influence platelet reactivity following a loading dose of 600 mg of clopidogrel and aspirin treatment [32]. Similarly, Gaborit et al have found no
ED
correlation between platelet reactivity and glycemic control parameters in diabetic patients on clopidogrel. Furthermore, in 15 poorly controlled type 2 diabetic patients,
PT
optimal glycemic control for one week did not modify platelet test results [33]. In contrast, Demirtunc et al have found a positive association between 3 months of
CE
improved glycemic control and mean platelet volume in type 2 patients with baseline
AC
HbA1c>7%. They however did not perform platelet aggregation tests. Notably the mean duration of diabetes was shorter than in the current study (5.9±4.8 years) [36]. Aoki et al have demonstrated significantly higher platelet-dependent thrombin generation in patients with poorly controlled non-insulin-dependent DM without complications (HbA1c > 9%) than in well controlled diabetic patients without complications (Hb A1c < 9 %) [16]. Although high platelet reactivity in patients with diabetes has been attributed among other factor to hyperglycemia [20,21] we did not detect a significant reduction in ADP-induced platelet aggregation (5 and 10 µM), arachidonic acid aggregation test or in soluble P-selectin levels after the achievement of better glycemic control in patients with longstanding poorly controlled DM.
ACCEPTED MANUSCRIPT One possible explanation is that hyperglycemia plays only a minor role in platelet reactivity in patients who have had high levels of glycemia for many years, and that
PT
other factors associated with DM contribute more to platelet reactivity, such as inflammation, insulin resistance and obesity. Notably, metabolic characteristics
SC RI
including obesity did not differ between the baseline and the post-glycemic control period. Another explanation might be that although there was a significant reduction in HbA1c level, most patients did not achieve a target HbA1c of 7% or less and hence
NU
optimal glycemic control was not achieved in the majority of patients.
MA
It is noteworthy that the baseline platelet aggregation values and P-selectin levels observed in the current study were similar to values of control patients taking aspirin
ED
from a previous study performed by our lab [37].
PT
Our study has several limitations. The main limitation is that the original target HbA1C of 7% was not met in most patients. However, all patients achieved a
CE
significant reduction in HbA1C level (a mean decrease of 1.4%), which was not
AC
associated with a reduction in platelet reactivity. Another limitation is that the regimen aimed at achieving glycemic control differed between the patients and consisted of various medications with or without insulin, as well as changes in diet, physical activity and glucose monitoring. Insulin, for instance, may have direct effects on the inflammatory system [35], which in turn affects platelet reactivity. Finally, the sample size was relatively small. In conclusion, this study showed that intensive glycemic control in patients with longstanding uncontrolled diabetes does not seem to result in a reduction in platelet reactivity. Further investigation is required to validate these findings, and to seek
ACCEPTED MANUSCRIPT alternative strategies to manage platelet hyper-reactivity in patients with type 2
AC
CE
PT
ED
MA
NU
SC RI
PT
diabetes.
ACCEPTED MANUSCRIPT Table 1. Baseline Characteristics
59.9±13.3
Women
7 (23.3%)
BMI (kg/m2)
32.21±8.04
Hypertension
21 (70%)
Dyslipidemia†
28 (93.3%)
Current smoking
4 (13.3%)
NU
SC RI
Age (years)
14 (46.6%)
Prior MI
21 (70%)
MA
Prior PCI
7 (23.3%)
Prior CABG
3 (10%)
Baseline Medications
PT
Aspirin
AC
CE
Statins
Beta blockers
ED
Prior stroke
Clopidogrel
PT
Demographic characteristics
ACE inhibitors / ARB
30 (100%) 30 (100%) 6 (20%) 22 (73.3%) 27 (90%)
† Diagnosis previously made by physician or receiving lipid-lowering therapy BMI = body mass index; MI = myocardial infarction; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; ACE = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers
ACCEPTED MANUSCRIPT Table 2. Clinical characteristics
Type I DM
6 (20%)
Disease
20.5±9.3
PT
Clinical Characteristics
12 (40%)
Retinopathy*
13 (43.3%)
Nephropathy*
24 (80%)
Peripheral
5 (16.6%)
NU
Neuropathy*
SC RI
duration (years)
vascular disease
23 (76.6%)
MA
Coronary artery disease†
Baseline 92.8±14
Medications
Baseline
3-4 months
Sulfonylurea
9 (30%)
6 (20%)
PT
ED
Weight (kg)
Post 93.1±14
22 (73.3%)
23 (76.6%)
1 (3.3%)
0
2 (6.6%)
2 (6.6%)
Insulin (any)
22 (73.3%)
26 (86.6%)
Insulin pump
2 (5.7%)
2 (5.7%)
3.8±1
3.7±1
80.9±45
78.6±41
49% / 51%
54% / 46%
Glitazones
CE
Metformin
AC
GLP-1 agonists
Insulin injections/day** Total daily insulin (units) Proportion of short / long acting insulin
* diagnosis made by treating physician; † history of myocardial infarction or coronary angiography demonstrating significant stenosis; ** in patients treated with insulin injections; BMI = body mass index; GLP-1 = glucagon-like peptide-1
ACCEPTED MANUSCRIPT Table 3. Laboratory parameters Laboratory Parameter
Baseline
After Intensive
PT
Glycemic Control 9.4±0.8 *
8.1±0.8 *
Hemoglobin (g/dL)
13.7±1.4
13.3±1.3
Platelets (103/mm3)
248±62
WBC (103/mm3)
7.5±2.2
Creatinine (mg/dL)
0.9±0.3
SC RI
HbA1c (%)
245±64 7.6±2.6
NU
0.9±0.3
73.5±23.2
80.1±25.2
HDL-c (mg/dL)
46.0±13.0
47.7±13.5
Triglycerides (mg/dL)
190±166 †
MA
LDL-c (mg/dL)
146±95 †
* P
