Cardio-cerebrovascular complications in elderly with diabetes

Archives of Gerontology and Geriatrics 44 (2007) 261–269 www.elsevier.com/locate/archger

Cardio-cerebrovascular complications in elderly with diabetes Massimo Motta a, Ettore Bennati a, Laura Ferlito a, Michela Passamonte a, Santo Branca b, Luciano Motta a,*, Mariano Malaguarnera a a

Department of Longevity Sciences, Urology and Neurology, University of Catania, Cannizzaro Hospital, Via Messina, 829, I-95124 Catania, Italy b ASL 3, Unita` Operativa di Geriatria, Ospedale S.Marta e S.Venera, 95024 Acireale (CT), Italy Received 16 January 2006; received in revised form 12 May 2006; accepted 15 May 2006 Available online 14 August 2006

Abstract Authors have considered the prevalence of hypertension (HT), myocardial infarction (MI) and stroke (S), in elderly subjects with diabetes, impaired fasting glucose (IFG) and normal fasting glucose (NFG), respectively. A high occurrence of diabetes in elderly subjects has been found. MI and S were more frequent in diabetic group than in IFG and NFG ones. HT proved to be elevated in the total pool, especially in older olds, and with a higher prevalence among those with diabetes. A 5-year follow-up has been carried out. The index of survival for MI and S was lower in subjects with diabetes. The subjects affected by both MI and S displayed the worst index of survival in all the three categories considered, therefore, it can be stated that such an association is a determinant factor of mortality. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetes mellitus; Impaired fasting glucose; Myocardial infarction; Ischemic stroke

1. Introduction Several studies documented an increasing prevalence of chronic vascular complications in subjects with diabetes. However, various studies of prevalence are not comparable, because they had been carried out on non-representative samples of the population, the involved subjects had been enrolled with different diagnostic criteria, and * Corresponding author. Tel.: +39 095 726 2050; fax: +39 095 498 811. E-mail address: [email protected] (L. Motta). 0167-4943/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2006.05.005

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derived mostly from particular environments or health care structures (e.g., hospitals, various institutions, outpatients services, etc.), or on a treatment-selective basis (Stolk et al., 1997; Turner et al., 1998; Davis et al., 1999; Zoppini et al., 2003; Fox et al., 2004; McEwan et al., 2004). In medical literature there are some studies carried out on non-selected groups of diabetic subjects, which report the mortality rate for cardiovascular disease, in which the new diagnostic criteria for diabetes are applied, and whose results have been compared to those related to population-based pools. Roper et al. (2002) described a significant decrease of cardiovascular mortality in type 2 diabetes with advancing age. As regards to the mortality gender ratio, the results are not homogeneous, however the risk of mortality for cardiovascular disease seems to be higher in diabetic females than in males (Gu et al., 1999). Saydah et al. (2002) reported that while in non-diabetic subjects the risk of mortality for cardiovascular disease is higher in males than in females, this ratio is the opposite among diabetic subjects. The mortality rate of ischemic stroke (IS) proved to be lower than that of the MI, however, it is higher in the diabetics than in the non-diabetics (Bogousslavsky, 1999; Mankovsky and Ziegler, 2004). As regards the short-term mortality, Megherbi et al. (2003) had performed an extensive, multicentric, prospective study on a large number of elderly subjects admitted because of S of various types. In that study the occurrence of the IS was significantly higher in diabetic patients, as compared to the non-diabetics. Nevertheless, after 3 months, the mortality rates were not significantly different between the diabetics and non-diabetics. This means that diabetes does not cause an increase of S mortality in short-terms. On the other hand, the age, male sex and the severity of the ictus contributed significantly to the short-term mortality. The poor availability of population-based studies on the cardio-cerebrovascluar complications in elderly with the new diagnostic criteria for diabetes induced us to study the prevalence of MI and S in a pool of elderly subjects, divided in three categories: (i) subjects with diabetes, (ii) subjects with IFG; (iii) subjects with NFG. All the subjects come from a population-based study carried out on a representative sample of the population (Maggi et al., 1994; ILSAWorking Group, 1997). Furthermore, we considered, in a 5-year follow-up, the survival and the significance of the contemporary presence of MI and S.

2. Research design and methods Our investigations were carried out on the subjects involved in the epidemiological studies of Italian Longitudinal Study on Aging (ILSA) Working Group, in the age-range of 65–84 years, using internationally validated criteria, elsewhere described (Maggi et al., 1994; ILSA Working Group, 1997). This retrospective study-population consisted of subjects which well describe the older Italian population in terms of risk factors and health determinants (Farchi et al., 2004). The ILSA Working Group started the studies in 1992 and completed in 2002, and was carried out by 8 centers. At baseline, a random sample of 5632 elderly subjects was selected; a clinical record has been filled in for each of them, a series of laboratory and

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instrumental analyses as well as various clinical tests have been performed, the arterial blood pressure was determined using previously described criteria (Maggi et al., 1994). In the present study we considered 3475 subjects who accepted to undergo all the specialized evaluations (e.g., endocrine-metabolic, cardiological and neurological). The diagnosis of MI was established on the basis of clinical data and of the electro-cardiographic (ECG) examination carried out on all patients. The diagnosis of S was established on the basis of the clinical history, of the neurological objective examination, and wherever it was possible, of the brain computerized tomographic (CT) scans. The subjects were classified according to the diagnostic criteria of American Diabetes Association (ADA) (Genuth et al., 2003) in diabetics (glycemia 126 mg/dl), subjects with IFG (100 mg/dl  glycemia <126 mg/dl), and normal subjects (glycemia <100 mg/dl). Concerning those subjects which displayed a 126 mg/dl  IFG < 140 mg/dl and without a clinical history of diabetes, no specific dietary indications nor drugs were ever administered (since baseline to follow-up), given the period in which the study was carried out. At last, we evaluated the vascular complications in relationship with the age factor, subdividing the pool in ‘‘younger olds’’ (age-range 65–74 years) and ‘‘older olds’’ (range 75–84 years). In the first group there were 1821 subjects, while in the last one we had 1654. It should be emphasized that this age-classification regards always the age at start of the studies, and kept in the description of the 5-year follow-up. Because of using different diagnostic criteria for diabetes, and of considering different numbers of subjects, the prevalence values given in the present paper are somewhat different from those described by the ILSA Working Group (1997). We performed also a follow-up study after 5 years on a total of 1943 subjects. Of the missing subjects, 881 died, 364 refused, 287 changed address, therefore, could not be contacted either by mail, phone or home visit. Death cases were ascertained on the basis of the data provided by the local Town Hall Archives. The study was performed according to the Helsinki Declaration and written informed consent was obtained from each participant. The criteria of protection of private rights have been strictly respected. Statistical evaluation has been carried out by using the x2-test for the 2  2 tables, and the t-test for independent samples, using a software ‘‘Primit.exe 3.03 Version’’ for Windows 2000. Statistical significance limit was put to p < 0.05.

3. Results and discussion The distribution of the elderly subjects in various categories at the baseline is presented in Tables 1–4. We should like to point out to the following main findings. (i) The prevalence values of MI and of S were in the total pool 9.0 and 7.8%, in the diabetic subjects 11.3 and 10.6%, respectively (Table 1). In the IFG subjects 8.0%, and 8.0% were observed, while for the NFG subjects the same values were 8.5 and 7.0%, respectively (Table 1). Comparing these data with literary ones (Garber, 2000; Ali Raza and Movahed, 2003; Nesto, 2004), one can establish that the diabetic subjects present significantly higher prevalence of MI and S, than the non-diabetic

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Table 1 Prevalence of MI and S in the elderly Total population

Data of total pool n %

Subjects with MI

Subjects with S

65–84a 65–74a 75–84a 65–84a

65–74a 75–84a

65–84a

65–74a 75–84a

3475 100.0

1821 52.4

1654 47.6

313 9.0

155 8.5

158 9.6

271 7.8

105 5.8

166 10.0

663 19.1

356 19.6

307 18.6

75 11.3

45 12.6

30 9.8

70 10.6

30 8.4

40 13.0

2500 71.9

1269 69.7

1231 74.4

213 8.5

100 7.9

113 9.2

176 7.0

61 4.8

113 9.3

312

196

116

25

10

15

25

15

10

8.0

5.1

12.9

8.0

7.1

D n % NFG <100 mg/dl n % 100 mg/dl  IFG < 126 mg/dl %

9.0

10.8

Statistical comparison x2-test, p a

7.0

D/NFG D/IFG 0.032 0.141

IFG/NFG D/NFG D/IFG 0.845 0.003 0.257

9.5 IFG/NFG 0.608

Age (years).

ones (Table 1). This demonstrates and confirms that diabetes, especially that of long duration, is an important pathogenetic factor for the cardio-cerebrovascular complications, above the risks due to the age itself. (ii) Table 1 presents also the prevalence values of MI and S for the younger (65–74 years) and older (75–84 years) groups. The observed prevalence values for both parameters in the younger group were lower, while in the older group were higher, than the averages of the total study pool (Table 1). At the same time, the diabetics in the younger group were more frequently touched by MI, than the diabetic subjects in the older age-group (Table 1), whereas the prevalence of S behaved in opposite manner between the younger and older groups of diabetics (Table 1). (iii) Table 1 presents also the results regarding both the NFG and IFG groups. These were in part similar to the tendencies of the total pool, or of the diabetic group, respectively, and there were also some differences between the trends observed in the MI and S prevalence values with advancing age. Nevertheless, statistically significant differences were found only in the D/NFG comparisons in both the MI and S (Table 1). Table 2 Occurrence and distribution of the associations of MI, S and HT in various classes of the elderly (number of cases) Age-groups

All together (28, 0.8%) D (6, 0.9%) IFG (4, 1.3%) NFG (18, 0.7%)

Total pool

65–74 years

75–84 years

H

N

H

N

H

N

21 5 3 13

7 1 1 5

11 3 2 6

1 1 0 0

10 2 1 7

6 0 1 5

H, hypertensive; N, non-hypertensive.

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Table 3 Sex-distribution of prevalence and acute mortality of MI, n (%) Diagnostic groups

Total pool

Males

Females

All pool Presence of MI Acute death cases

3475 (100.0) 313 (9.0) 73 (23.3)

1815 (52.2) 221 (12.2) 51 (23.1)

1660 (44.8) 92 (5.5) 22 (23.9)

D

663 (19.1) 75 (11.3) 21 (28.0)

329 (49.6) 51 (15.5) 15 (29.4)

334 (50.4) 24 (7.2) 6 (25.0)

IFG Presence of MI Acute death cases

312 (8.1) 25 (8.0) 8 (32.0)

170 (54.5) 18 (10.6) 6 (33.3)

142 (45.5) 7 (4.9) 2 (28.6)

NFG Presence of MI Death cases

2500 (71.9) 213 (8.5) 44 (20.7)

1316 (52.6) 152 (11.6) 30 (19.7)

1184 (47.4) 61 (5.2) 14 (23.0)

(IGF) = 0.724 (D/NGF) = 0.064 (D/NGF) = 0.196 (IGF) = 0.804 (D/NGF) = 0.062 (D/NGF) = 0.933

(NFG) < 0.001 (IFG/NFG) = 0.808 (IFG/NFG) = 0.960 (NFG) = 0.736 (IFG/NFG) = 0.303 (IFG/NFG) = 0.890

Presence of MI Acute death cases

Statistical comparisons by the x2-test, p Prevalence for M/F (D) = 0.001 Prevalence for M (D/IFG) = 0.171 Prevalence for F (D/IFG) = 0.475 Mortality for M/F (D) = 0.903 Mortality for M (D/IFG) = 0.990 Mortality for F (D/IFG) = 0.764

Table 2 shows the results regarding the association of MI, S and HT in the study population. We observed 28 subjects (0.8%) in the total pool with associated MI and S, and 21 of them (75.0%) had also HT (Table 2). When distributing these cases in the age and disease classes, we find only small numbers of cases per class, therefore, it is not very useful to make percentual evaluations (Table 2). Table 3 describes the sex-dependent distribution of the occurrence and mortality of MI. It is interesting to note that the prevalence of MI is significantly higher in males than in females, while the mortality rates are very close to each other in both sexes (Table 3). The increased prevalence of MI in the males, observed by us in all categories, in agreement with Roper et al. (2002), proves that the male sex is also an independent risk factor of MI. The prevalence values of HT in various groups are shown in Table 4. Almost 30% of the total pool had HT, somewhat more in the younger age group and somewhat less in the older age group (Table 4). Similar values were found in the NFG group, while both the diabetics and the IFG groups displayed higher prevalence of HT (Table 4). The S seems to be particularly related not only to diabetes, but also to age factor. In fact, comparing the prevalence of S between younger olds and older olds, it is clearly higher in the latter age-group, independently from the glycemic status, and this difference is highly significant ( p < 0.001). From the analysis of data found in the IFG subjects, the prevalence values of both the MI and S were not statistically different from those of NFG; however, there seems to be some kind of interaction between MI prevalence, IFG status and age (Table 4).

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Table 4 Prevalence (%) of HT in various groups of the elderly Total pool

65–74 years

75–84 years

Normotensives All HT Isolated systolic HT The rest

29.3 70.7 60.6 39.4

31.6 68.4 56.5 43.5

26.8 73.2 66.6 33.4

In D Normotensives All HT Isolated systolic HT The rest

22.9 77.1 67.1 33.0

24.5 75.5 66.7 33.3

21.0 79.0 67.5 32.5

IFG Normotensives All HT Isolated systolic HT The rest

23.4 76.6 61.9 38.1

24.5 75.5 47.3 52.7

21.6 78.5 67.0 33.0

NFG Normotensives All HT Isolated systolic HT The rest

31.5 68.5 61.2 38.8

34.5 65.5 55.4 44.6

28.5 71.5 65.4 34.6

Statistical comparison x2-test, p

(D/NFG) <0.001

(D/IFG) =0.933

(IFG/NFG) =0.004

At the follow-up investigation, the main observations, which should be considered, are the following: (i) The incidence of new cases of diabetes was 4.8% in IFG subjects and 0.7% in NFG. Table 5 displays the prevalence of MI, S and of HT. MI and HT are particularly related to diabetes. (ii) The mortality of subjects with MI and S are displayed in Table 6. The global mortality of subjects with MI was 23.3%. This mortality rate was higher in diabetics compared to NFG (28.0% versus 20.7%). Mortality data of the subjects having had a stroke are also higher in diabetics than NFG (32.3% versus 27.3%) (Table 6). (iii) The sex-dependent mortality rates in subjects with MI were higher in male diabetics, compared to females ones (29.4% versus 25.0%), while this ratio is Table 5 Prevalence of MI, S and HT at the follow-up investigation Groups

Total D IFG NFG

Subjects

MI

S

HT

n

%

n

%

n

%

n

%

1943 360 181 1402

100.0 18.5 7.3 74.3

181 47 14 120

9.3 13.1 10.3 8.5

138 29 17 92

7.1 8.1 9.4 6.6

73.40 80.7 74.0 71.4

26.6 18.3 26.0 28.6

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Table 6 Mortality of subjects with MI and S at the 5-year follow-up Groups

Total D IFG NFG

With MI (1992)

313 75 25 213

Present at follow-up

113 22 4 87

Died n

%

73 21 8 44

23.3 28.0 32.0 20.7

Absent, n

New cases

127 32 13 82

74 25 10 39

Statistical comparisons of mortality with MI, x2-test, p (D/NFG)

(D/IFG)

(IFG/NFG)

At start At follow-up

0.899 0.892

0.297 0.493

0.251 0.227

Groups

With S (1992)

Present at follow-up

Died n

%

Total D IFG NFG

271 70 25 176

113 18 15 80

76 24 4 48

28.0 32.3 16.0 27.3

Absent, n

New cases

82 28 6 48

32 10 6 16

Statistical comparisons of mortality with S, x2-test, p (D/NFG)

(D/IFG)

(IFG/NFG)

At start At follow-up

0.143 0.694

0.337 0.012

0.350 0.047

inverted in NFG group (19.7% in male NFG subjects versus 23.0% in females, data not shown). (iv) The subjects having had both MI and S displayed a mortality of 42.7% in the total study pool. It was 50.0% in the diabetics, 75.0% in the IFG group, and 33.3% in the NFG group (Table 7). The follow-up of 5 years did not reveal any particular difference in the prevalence of diabetes, as compared to the baseline, in spite of the occurrence of newly diagnosed diabetic cases. This is due to the compensation by the death cases against the new ones. The new cases of diabetes during 5 years amounted to 4.8% in the IFG subjects, while in the NFG group it is only 0.7% ( p < 0.001). This seems to agree with the opinion that IFG has a certain predictive meaning for diabetes (Unwin et al., 2002). Table 7 Mortality of subjects having both MI and S at the 5-year follow-up Groups

Total D IFG NFG

With MI + S (1992)

28 6 4 18

Present at follow-up

12 2 1 9

Died n

%

12 3 3 6

42.7 50.0 75.0 33.3

Absent, n

New cases

4 1 0 3

13 5 3 5

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The specificity of IFG in the assessment of the metabolic status in the elderly population has not yet been proven. On the contrary, our previous studies demonstrated that there were IFG subjects who after 5 years not rarely displayed normal glycemia levels without any particular therapeutic intervention (unpublished data). Consequently, frequent control of glycemia, especially post-prandial ones, and other markers to increase the predictive sensibility and specificity of diabetes (i.e., insulin-resistance, adiponectin, etc.) should be performed. As regards the MI, according to literature data (Gu et al., 1999; Roper et al., 2002), comparative analysis after 5 years demonstrated a larger increase of mortality in diabetic subjects compared to the NFG group. However, in our studies, there was only a slightly significant difference ( p < 0.05, Table 6). This finding limits, at least in shorter time intervals, the unfavorable prognostic value of D in the evolution of MI in the elderly. Concerning the sex-dependent mortality, it displayed in our study pool higher values in male diabetics ( p = 0.903, NS), while in the NFG subjects it was higher in the females ( p = 0.736, NS) (Table 3). It could mean that while the MI itself is sex-related to a certain extent, its lethal outcome is independent from this factor. The data related to the IFG subjects are of difficult interpretation. It is partially due to the relatively low sample size. The mortality of both MI and S could be considered as being higher in the IFG subjects after 5 years, than in the NFG group. These last results seem to be in agreement with other previous findings, according to which the altered glucose metabolism may form a basis for an increased incidence and severity of MI (Lim et al., 2000; Unwin et al., 2002). The mortality for S was also higher in the diabetics than in the NFG group after 5 years. In the IFG subjects the manifestations of S were only of low significance. On the other hand, it seems to be of great importance that only a low percentage of contemporary presence of MI and S was observed. This prevalence overlaps in elderly diabetics, IFG and NFG subjects. These findings prove that association of MI with S does not permit a long survival in the elderly. If one evaluates the blood pressure values, it can be established that the prevalence of HT is age- and also diabetes-correlated. It is significantly higher in the older than in the younger age group of our study pool ( p = 0.002). The prevalence of HT, especially of the isolated systolic one, is significantly higher in diabetic subjects compared to NFG ( p < 0.001, Table 4).

4. Conclusion Diabetes causes a major prevalence of Myocardial Infarction or Stroke in the elderly. Stroke prevails in the older age group, demonstrating a closer age-dependence for cerebrovascular complications, other than diabetes. Mortality rates of these single complications display significant differences in relation with the metabolic alterations. The association of MI and S represents an evidently high lethality in all 3 groups studied. The severity of this association prevails on the effects of diabetes itself on mortality.

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