Jurnal 3
Jurnal 3
  Abstract 
  Background:  Diabetics have increased risks for cardiovascular disease (CVD) and mortality, reducing their life
  expectancy by up to 15 years. Type 2 diabetes mellitus specifically increases the risk for cardiovascular mortality nearly
  fivefold. When hypertension is combined with diabetes, the risk of CVD is even greater.
  Objective:  Identify non-fatal cardiovascular outcomes and renal function impairment in a cohort of hypertensive
  patients in regular treatment in a reference treatment center, over 11 years of follow-up.
  Methods:  Historical cohort of hypertensive patients in regular treatment for at least 11 years in a specialized service
  for hypertension treatment. The exposed group was hypertensive diabetic patients at the beginning of the cohort,
  and the non-exposed group had hypertension without diabetes. The cohort began in 2004, with follow-ups in 2009
  and 2015. Variables used: gender, race, age, physical activity, alcohol consumption, smoking, blood pressure, body
  mass index, glycated hemoglobin, diabetes and hypertension diagnosis times, treatment time in specialized service,
  non-fatal cardiovascular outcomes, and renal impairment assessed by creatinine clearance.
  Results:  139 patients participated in the study (55 diabetic hypertensive; 84 non-diabetic hypertensive), with an ini-
  tial (2004) mean hypertension treatment time of 5.8 years. Females were the majority (75.5%) in both groups. Groups
  were similar regarding socio-demographic variables, but the group of hypertensive diabetic patients had higher
  frequency of obesity and uncontrolled BP, which persisted in all follow-ups. In 11 years of follow-up (2004–2015),
  the diabetic group had more cardiovascular events, with increased risk of acute myocardial infarction (RR 95% CI 1.6
  12.2–95.0), stroke (RR 95% CI 1.3–6.1 27.7) and complications requiring hospitalization (RR 95% CI 1.6 2.2–3.0). Wors-
  ened renal function occurred more often in the non-exposed group, but in the end, the proportion of renal function
  loss was similar between groups.
  Conclusions:  Exposure to type 2 diabetes increased the risk of new cardiovascular outcomes over 11 years of follow-
  up of hypertensive patients. Diabetes by itself increased the risk of cardiovascular outcomes, justifying more intensive
  actions in this population.
  Keywords:  Hypertension, Type 2 diabetes mellitus, Cardiovascular diseases, Diabetes complication
*Correspondence: andrea.c.sousa@hotmail.com
2
  Hypertension League, Federal University of Goiás (Universidade
Federal de Goiás), 1ª Avenida, S/N‑Setor Leste Universitário, Goiânia, GO
74605‑020, Brazil
Full list of author information is available at the end of the article
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Sousa et al. Diabetol Metab Syndr (2017) 9:98                                                                                          Page 2 of 9
Background
                                                                                           Medical records survey
Hypertension (HTN) is a well-established risk factor for                                           in 2014
the other hand, type 2 diabetes (T2DM) is an independ-                71 diabetic              270 non-diabetic       84 Diagnosed with DM in
ent risk factor for cardiovascular diseases such as athero-          hypertensive                hypertensive             10 years interval
                                                                                                                     *CKD was not identified at
sclerosis and heart failure [2]. T2DM increases the risk of                                                          the beginning of the cohort
collected for biochemical analysis. The reference values       square test or Fisher’s exact test, as needed. Quantita-
were creatinine  <  1.3  mg/dL, lipid profile (total choles-   tive variables are presented with their means, stand-
terol  <  200  mg/dL; LDL cholesterol  <  100  mg/dL; HDL      ard deviation, median and confidence interval. Means
cholesterol  >  60  mg/dL) [8], glucose (≤  130  mg/dL for     were compared with Student’s T test only after analy-
diabetic hypertensives and  <  110  mg/dL for the general      sis of data distribution with the Kolmogorov–Smirnov
population), and HbA1C (≤ 7%) [9].                             test.
   The classification used for the body mass index               The relative risk of each outcome conferred by expo-
was (a) underweight (BMI  <  18.5  kg/m2); (b) nor-            sure to T2DM was calculated in the form of a 95% con-
mal (BMI  =  18.5–25  kg/m2); (c) overweight                   fidence interval. Adjusted analysis was performed for all
(BMI  =  25–29.9  kg/m2); (d) obesity (BMI  ≥  30  kg/m2)      predictors, with a significance level of  <  0.20 in bivari-
[10].                                                          ate analysis, considering each outcome as dependent
   Cardiovascular outcomes were defined as non-fatal           variable.
myocardial infarction (MI), myocardial revasculariza-            All tests were considered at a significance level of 5%
tion, stroke, acute coronary syndrome, hospitalizations        and a confidence interval of 95%.
and blood pressure uncontrolled. Fatal events were not
considered outcomes because this was a non-concur-             Results
rent cohort, whose composition was determined by               We selected 71 diabetics (exposed group) and 84
whether patients were in regular treatment in the base         non-diabetic hypertensive patients (non-exposed
year (2015). Medical records were analyzed to iden-            group) for study participation. Among the diabetics,
tify cardiovascular outcomes that occurred between             12 were excluded due to follow-up loss, since they
the first and the second evaluation (2004–2009). In            did not attend their appointments in the final follow-
the last evaluation (2015), the participants visited the       up. Thus, in 2015, 139 patients agreed to participate
office and were asked about the occurrence of events.          in the study. Among them, 55 were hypertensive dia-
At this time, the medical records were evaluated again         betics, and 84 were hypertensive non-diabetics. At
to verify the reliability of the information provided by       the beginning of the cohort, the mean age in both
patients.                                                      groups was similar (57.5  ±  9.3  years). The antihy-
   For evaluation of renal impairment, we used the cre-        pertensive treatment time in the service was also the
atinine clearance, determined by the Cockcroft–Gault           same in the two groups (5.9  ±  3.9  years). However,
equation. For purposes of analysis, the estimation             the average time from diagnosis of hypertension was
of glomerular filtration rate (GFR) was used con-              significantly different (16.5  ±  9.5  years for the dia-
sidering the following categories: normal  ≥  90  mL/          betic group vs. 12.2  ±  7.32  years for non-diabetics;
min/1.73  m2, mild kidney failure 60–89  mL/                   p  <  0.05). The average time from diagnosis of DM
min/1.73  m2, moderate kidney failure 30–59  mL/               was 4.0  ±  6.0  years. The groups at the beginning of
min/1.73  m2, severe kidney failure 15–29  mL/                 the cohort (2004) were similar regarding socio-demo-
min/1.73  m2 and terminal renal insufficiency                  graphic variables, except the group of hypertensive
(CRI) < 15 mL/min/1.73 m2. In addition to that, these          diabetic patients had higher frequencies of obesity
categories were dichotomized with a cutoff point               (45.5%) and uncontrolled blood pressure (76.4%)
of  >  60  mL/min/1.73  m2 for normal kidney function          (Table 1).
or mild damage, and below this value was considered              In 11  years of follow-up, both groups decreased
moderate, severe or chronic renal failure [11].                diastolic blood pressure, total cholesterol, low-density
                                                               lipoproteins (LDL), triglycerides and creatinine clear-
Statistical analysis                                           ance. Among the hypertensive diabetics in the same
The qualitative variables are presented with their             period, there was a significant increase in high-density
absolute frequencies and proportions. The asso-                lipoproteins (HDL) and a reduction in triglycerides
ciations between them were measured with the Chi               (Table 2).
Sousa et al. Diabetol Metab Syndr (2017) 9:98                                                                                 Page 4 of 9
Sex                                                                                                                              0.420
     Male                                       11              20.0            23              27.4           34      24.5
     Female                                     44              80.0            61              72.6           105     75.5
Ethnicity                                                                                                                        0.857
     White                                      30              57.7            42              54.5           72      55.8
     Non-white                                  22              42.3            35              45.5           57      44.2
     No record                                  3                5.5            7               8.3            10       7.2
Age (years)                                                                                                                      0.804
     < 50                                       12              21.8            22              26.2           34      24.5
     50–60                                      22              40.0            30              35.7           52      37.4
     60–70                                      17              30.9            23              27.4           40      28.8
     > 70                                       4                7.3            9               10.7           13       9.4
Physical activity                                                                                                                0.488
     Regular                                    30              55.6            47              56.0           77      55.8
     Irregular                                  5                9.3            13              15.5           18      13.0
     Absent                                     19              35.2            24              28.6           43      31.2
     No record                                  1                1.8            0               0.0            1        0.7
Smoking                                                                                                                           0.430
     Yes                                        1                1.8            5               6.0            7        4.5
     Former                                     21              38.2            27              32.1           48      34.5
     Never                                      33              60.0            52              61.9           85      61.2
Alcohol consumption                                                                                                               0.107
     Yes                                        1                1.8            7               8.3            8        5.8
     No                                         54              98.2            77              91.7           131     94.2
Number of antihypertensive drugs                                                                                                  0.811
     0–1                                        17              30.9            24              28.6           41      29.5
     2–3                                        37              67.3            57              67.9           94      67.6
     4+                                         1                1.8            3               3.6            4        2.9
                           a
Blood pressure control                                                                                                          < 0.001
     Yes                                        13              23.6            48              57.1           61      43.9
     No                                         42              76.4            36              42.9           78      56.1
Lipid-lowering agent use                                                                                                         0.302
     Yes                                        6               10.9            3               3.6            9        6.5
     No                                         49              89.1            81              96.4           130     93.5
Body mass index                                                                                                                  0.003
     Normal                                     9               16.4            27              32.1           36      25.9
     Overweight                                 21              38.2            41              48.8           62      44.6
     Obese                                      25              45.5            16              19.0           41      29.5
Glycemic controlb                                                                                                               –
     Yes                                        9               19.1            –               –              9       19.1
     No                                         38              80.9            –               –              38      80.9
* Pearson’s Chi square
a
  Blood pressure parameters: diabetic hypertensive < 130/80 mmHg and non-diabetic hypertensive < 140/90 mmHg
b
      HbA1C control ≤ 7%
Sousa et al. Diabetol Metab Syndr (2017) 9:98                                                                                                                Page 5 of 9
Table 2  Initial and final follow-up comparison of non-concurrent cohort according to groups (hypertensive diabetics
and non-diabetics) in laboratory and clinical parameters, Goiânia, GO, Brazil, 2004–2015
                    Diabetic hypertensive (n = 55)                                                Non-diabetic hypertensive (n = 84)
SBP                 139.0 (132.0–143.0)          134.0 (133.0–143.8)              0.586           130.7 (129.4–138.2)            131.0 (129.5–136.8)            0.742
DBP                  85.0 (81.9–89.8)             73.0 (71.8–77.8)              < 0.001           82.0 (81.7–87.4)               73.7 (71.8–76.3)               < 0.001
BMI                  29.3 (29.5–32.5)             29.3 (28.9–32.1)                0.080           26.3 (25.8–27.6)               27.1 (26.1–28.1)               0.081
GFR                 139.0 (136.1–167.5)          139.0 (129.8–167.5)              0.891           96.0 (92.2–99.5)               93.0 (91.5–98.1)                0.655
TC                  215.0 (200.9–229.8)          165.0 (157.2–184.8)            < 0.001           201.5 (198.3–218.1)            181.6 (175.4–188.8)             < 0.001
HDL                  47.0 (43.6–51.5)             51.0 (49.2–56.2)                0.009           47.0 (45.0–50.3)               48.0 (45.7–51.2)                0.056
LDL                 126.0 (111.5–197.3)           85.3 (80.4–95.3)              < 0.001           129.5 (125.3–141.2)            112.0 (103.2–115.1)             < 0.001
TG                  179.0 (169.4–257.1)          134.0 (117.3–249.8)              0.024           110.5 (119.5–163.7)            114.0 (113.9–140.9)             0.825
CC                   82.9 (76.7–87.7)             64.2 (62.2–79.1)              < 0.001           70.2 (70.5–80.2)               61.9 (60.3–71.7)                < 0.001
HbA1c                 9.2 (5.0–15.0)                  7.4 (5.5–13.3)              0.002           –                              –                               –
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, GFR glomerular filtration rate, TC total cholesterol, HDL HDL cholesterol, LDL LDL
cholesterol, TG triglycerides, CC creatinine clearance, HbA1c hemoglobin, 95% CI 95% confidence interval
** Mann–Whitney U test
  In the final evaluation of this cohort, 43.6% of hyper-                             renal impairment among the non-diabetic hypertensive
tensive diabetics showed renal impairment (creatinine                                 group. This group initially showed 60.7% of participants
clearance < 60/min/1.73 m 2) and 45.2% of the non-dia-                                with mild renal lesion (60–89  mL/min/1.73  m2), and
betic group; in other words, between the initial and final                            19.0% could be considered within the range of normal
follow-up, the proportion of renal impairment increased                               (≥  90  mL/min/1.73  m2); in the diabetic group, the mild
significantly in both groups, but they stayed similar to                              impairment was 52.7%, and 32.7% had rates within the
each other (Table 3).                                                                 standards of normality. Both groups had increases in
  Renal function, assessed by the proportion of patients                              the frequency of those with moderate renal impairment
in the different categories, suffered significant changes                             (30–59  mL/min/1.73  m2) over the 11  years of follow-up
over the follow-up course. There was a greater rate of                                (Fig. 2).
 Fig. 2  Distribution of patients with different categories of renal function throughout the study period (2004–2015), Goiânia, GO, Brazil, 2004–2015.
 McNemar–Browker test: *p < 0.05
  Regarding cardiovascular outcomes, in the intermedi-                        risk of hypertensive diabetics raised in relation to the
ate evaluation, both groups showed similar occurrences                        non-diabetics.
of AMI, acute coronary syndrome, myocardial revascu-
larization and hospitalization. The proportion of hospi-                      Discussion
talizations in each group at the intermediate evaluation                      Our service is constituted in the Brazilian public health
surpassed 20%. However, the group of hypertensive dia-                        care system and is based on the attendance of a hyper-
betics had a higher incidence of stroke (exposed: n = 5,                      tensive population, aiming at pressure control and con-
9.1%; non-exposed: n  =  1, 1.2%), with a relative risk of                    sequently the prevention of cardiovascular outcomes,
7.6, counting the period of 5  years of follow-up from                        since diabetes mellitus and arterial hypertension cause
2004 (Table 3).                                                               diseases that entail high costs, both socially and econom-
  Regarding blood pressure control, diabetics showed                          ically. A multiprofessional team (doctors of various spe-
lower rates of control throughout the entire cohort                           cialties, nurses and nutritionists) performs our services,
(23.6, 27.3, and 29.1%, respectively) when compared                           but even so, this study showed a higher incidence and
to the unexposed group (57.1, 67.9, and 69.0%) in the                         risk of AMI, stroke, hospitalization and uncontrolled BP
three follow-ups (p < 0.05). The additional risk presented                    among hypertensive diabetics. Type 1 or 2 DM patients
by the diabetic group was 2.3 times higher than in the                        have CVD rates 4–10 times higher than non-diabetic
other group on the intermediate and final follow-ups                          individuals [12]. The occurrence of these outcomes is
(p < 0.001).                                                                  likely related to the interaction between the side effects of
  Overall, in 11  years of follow-up, the group of hyper-                     hyperglycemia in association with other risk factors, such
tensive diabetic patients presented more cardiovascular                       as hypertension, dyslipidemia and obesity [13].
events and a higher risk of cardiovascular events: the risk                      Diabetics who are even being treated for HAS and dys-
of AMI was 12.2 times greater, the risk of stroke was 6.1                     lipidemia still have an increased risk of CVD, showing
times greater, and the risk of hospital admissions was                        at least twice the risk of stroke and a death risk approxi-
2.2 times higher compared to non-diabetics (Table 3). In                      mately 20% higher compared to non-diabetic individu-
the adjusted analysis, no predictive variable was associ-                     als [14]. The relative risk for stroke in this study was six
ated with the outcomes analyzed. The diagnosis time of                        times higher among diabetic individuals. A cohort study
T2DM and treatment in the service were not associated                         in England, with duration of 5.5  years in 1,900,000 peo-
with the frequency of events.                                                 ple, showed that diabetics had a higher risk of ischemic
  Diabetic hypertensive patients had more cardiovas-                          stroke [15]. The same situation was identified in a cohort
cular complications and hospitalizations compared to                          study (17  years) of 10,582 Japanese, where the risk of
non-diabetic hypertensive patients. The main non-fatal                        non-embolic ischemic stroke was approximately two
outcomes found in our study were stroke, AMI, hospi-                          times higher in individuals with type 2 DM than in non-
talizations and uncontrolled blood pressure, with the                         diabetic individuals [16]. A meta-analysis involving 102
Sousa et al. Diabetol Metab Syndr (2017) 9:98                                                                  Page 7 of 9
prospective studies demonstrated that the adjusted risk      European patients had a rate of 8.4%, patients in South
rate for ischemic stroke was two times higher in diabetic    Asia had 6.0% and Chinese patients had 3.8% [22].
individuals [17]. We must consider that the study sample        DM is in itself an independent risk factor for coronary
consisted of hypertensive patients with an average age       artery disease, and the risk is dramatically higher when
above 60 years in the final analysis.                        hypertension is a comorbidity [23]. In this study, the dia-
   The time of DM exposure is also considered a risk fac-    betic patients had their best BP pressure control rate of
tor for stroke, indicating that each year of disease diag-   29.1% in the last follow-up. HTN affects approximately
nosis increases the outcome risk by up to 3% [18]. In this   70% of patients with diabetes and is approximately twice
study, there was no association between duration of DM       as common in people with diabetes [24]; it significantly
diagnosis and any outcome. We should emphasize that          increases the risk of vascular complications, predisposing
our patients were under treatment in a specialized ser-      these patients to chronic kidney disease (CKD) [25] and
vice, and the study sample was homogeneous.                  substantially increasing the risk of ischemic stroke [26].
   In 11 years of follow-up, the exposed group presented        There are still some uncertainties and controversies
12.2-fold higher risk to be affected by AMI. In the Eng-     over the BP reduction target in hypertensive patients,
lish cohort study mentioned above, non-fatal AMI risk        especially those above 60  years, who typically feature
was 1.5 times greater for the hypertensive diabetics [15].   higher levels of systolic blood pressure [27]. Recently,
Again our study found rates higher than those reported       the SPRINT study concluded that among hypertensive
in the literature and that may be related to the socio-      patients at high cardiovascular risk, but without dia-
demographic specificities of the study population from       betes, treatment aiming for a systolic blood pressure of
which the sample was selected. Clinical trials have shown    less than 120 mmHg, compared with blood pressure less
that simply improving glycemic control is unlikely to pre-   than 140 mmHg, resulted in lower rates of cardiovascular
vent the increased mortality after AMI in patients with      events and death [28], i.e., the lower the goals for blood
DM, because intensive glucose control cannot reduce          pressure control, the greater the benefits to be achieved
cardiovascular events, as well as the mortality rate in      in a population of non-diabetics hypertensive.
patients with DM [19]. The control of other risk factors,       Regarding diabetic hypertensive, BP goals have been
such as dyslipidemias, is considered more effective than     widely discussed, since there is no consensus if the same
glucose-lowering therapy to reduce the incidence of car-     goal of BP  <  140/90  mmHg should be applied. In the
diovascular events.                                          ACCORD study, with a population of hypertensive dia-
   Diabetics in this study showed bad glycemic control,      betics, intensive BP and glucose control was tested, and
although it improved over the follow-up time (16.4%          it demonstrated a reduction in the number of isolated
controlled initially vs 41.8% at the end of follow-up). On   strokes compared with controlling BP to a lower value
the other hand, they showed worse BP control rates. It       (120 mmHg). On the other hand, the number of serious
should be noted that stricter parameters were considered     adverse events increased as a result of the intensive treat-
for BP control among diabetics [20]. T2DM patient care       ment of hypertension and glycemia [29].
should be the result of integral management of cardio-          After the publication of the SPRINT study, in 2015, the
vascular risk, which includes other factors than glucose,    researchers of the ACCORD study supported the posi-
such as dyslipidemias, obesity and hypertension [3].         tion of the benefits of intensive reduction of systolic BP
   We observed a higher rate of hospitalization among        to < 120 mmHg in patients with high cardiovascular risk
hypertensive diabetics. A study evaluating the independ-     and that these goals should also be extended to hyperten-
ent contributions of HbA1c, systolic blood pressure and      sive diabetics, though they acknowledged some limita-
LDL cholesterol control to hospitalizations in patients      tions in their study of intensive control of blood glucose
with T2DM demonstrated that patients without control         and BP [30].
of these risk factors or with just the HbA1c controlled         In the present study, the hypertensive patients with-
showed the highest rates of cardiovascular hospitali-        out a diabetes diagnosis showed a worse evolution of
zation, while those with all risk factors controlled had     renal function. HTN is the most important independ-
the lowest rates. This same study showed that to keep        ent risk factor for renal involvement that is associated
SBP  <  130  mmHg or LDL-C  <  100  mg/dL was signifi-       with increased cardiovascular morbidity and mortality
cantly associated with reducing the risk of cardiovas-       [31]. Chronic kidney disease is the 18th cause of overall
cular hospitalization, but keeping HbA1c  <  7% did not      mortality [32]. In hypertensives, chronic kidney disease
translate to a reduction in CVD hospitalization risk [21].   (CKD) is less frequent than among diabetic patients [33],
Another study comparing rates of cardiovascular com-         but it is also considered harmful to the prognosis of the
plications that required hospital admission among dia-       disease [34]. Treating hypertension improves prognosis,
betic individuals from various countries revealed that       as it slows the progression of kidney disease [35]. Among
Sousa et al. Diabetol Metab Syndr (2017) 9:98                                                                                                              Page 8 of 9
T2DM patients, CKD occurs in 25–40% of patients [36],                              lipoproteins; GFR: glomerular filtration rate; TC: total cholesterol; TG: triglycer-
                                                                                   ides; CC: creatinine clearance; HbA1c: hemoglobin A1C; CHD: coronary heart
representing great morbidity and mortality, and is con-                            disease.
sidered one of the criteria that defines a patient at greater
risk of suffering future coronary events [37]. Hyperten-                           Authors’ contributions
                                                                                   All authors gathered data, reviewed and edited the manuscript and contrib-
sion, diabetes and dyslipidemia control are decisive in                            uted to discussions. All authors read and approved the final manuscript.
renal disease of diabetic and non-diabetic patients, aim-
ing to reduce cardiovascular events as well [38].                                  Author details
                                                                                   1
                                                                                     Nursing School, Federal University of Goiás (Universidade Federal de Goiás),
                                                                                   Goiânia, Brazil. 2 Hypertension League, Federal University of Goiás (Universi-
Limitations                                                                        dade Federal de Goiás), 1ª Avenida, S/N‑Setor Leste Universitário, Goiânia, GO
Because this is a retrospective study and the criteria for                         74605‑020, Brazil. 3 Medical School, Federal University of Goiás (Universidade
                                                                                   Federal de Goiás), Goiânia, Brazil.
inclusion were to be in regular treatment in our service
with an active chart, it was not possible to identify the                          Acknowledgements
casualties that may have occurred between the years of                             We thank the entire team of the Arterial Hypertension League HC/UFG.
2004–2015. However, that does not minimize the results                             Competing interests
of the study, since the objective was to compare the                               The authors declare that they have no competing interests.
occurrence of nonfatal outcomes in hypertensive diabetic
                                                                                   Availability of data and materials
patients to those who were hypertensive but without the                            The authors do not wish to share their data.
development of other morbidity.
   Another point to consider is that it has not been pos-                          Consent for publication
                                                                                   “Not applicable” in this section.
sible to analyze the correlations between the values of
blood pressure and the incidence of outcomes, because                              Ethics approval and consent to participate
we used chart registry data that did not allow the iden-                           All of the participants were voluntary recruits who freely agreed to participate
                                                                                   in the study. All participating patients signed a free and informed consent
tification of the BP values at the outcome time. This is                           form. The study conformed to the Declaration of Helsinki and was approved
an intrinsic limitation to non-concurrent cohort studies,                          by the Research Ethics Committee of the Clinical Hospital of the Federal
and only prospective studies would permit this assess-                             University of Goiás (Ruling No. 931,503).
ment. The cohort of participants in this study should                              Funding
remain under evaluation, with regular follow-ups that                              The present study had no funding from any research support agency.
will allow for assessing such results in the future.
                                                                                   Publisher’s Note
Conclusions                                                                        Springer Nature remains neutral with regard to jurisdictional claims in pub-
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Both groups showed cardiovascular outcomes, as well
as hospitalizations and renal impairment. However, an                              Received: 22 August 2017 Accepted: 24 November 2017
increased frequency of these outcomes was found among
the diabetic patients. Hypertensive diabetics, as a result
of metabolic and vascular damage, are more prone to car-
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