Cardiovascular Events and Geriatric Scale Scores in Elderly (70 Years Old and Above) Type 2 Diabetic Patients at Inclusion in the GERODIAB Cohort

The prevalence of diabetes in the elderly is growing because of both increased life expectancy and incidence of diabetes in the general population (1–3). Compared with younger diabetic patients, the cumulative consequences of diabetes and aging exacerbate degenerative complications and the effects of comorbidities (4,5). Elderly diabetic patients also make up a heterogeneous population, which bears little resemblance to younger diabetic patients and requires a patient-centered approach (6–8).

Numerous studies have analyzed the factors associated with macroangiopathic complications in type 2 diabetic patients under the age of 70 years. Associated, potentially explanatory factors are thus well-known, particularly the duration of diabetes, hypertension, hypercholesterolemia, and poor glycemic control (9,10). However, there is no clear evidence that such associations might be observed in elderly diabetic patients, because aging and associated comorbidities can modify the influence of classical cardiovascular risk factors, notably diabetes. In elderly diabetic patients, physical function is impaired. Autonomy is obviously impaired at advanced stages of cardiovascular disease in the elderly. However, there is no clear information about the impact of cardiovascular diseases on other geriatric parameters such as cognition, nutrition, and mood, notably in elderly diabetic patients (11).

Therefore, using information derived from diabetic patients aged ≥70 years from the GERODIAB cohort at study inclusion, we aimed to investigate the factors, including cognitive functions and geriatric syndromes, that are associated with coronary and cerebrovascular ischemia; heart failure; and coronary, cerebral, and vascular diseases of the lower limbs.

The GERODIAB study is a French multicenter, prospective, observational 5-year follow-up study designed to analyze glycemic control and morbidity/mortality in type 2 diabetic patients aged 70 years and older, with relatively preserved autonomy (activities of daily living [ADL] score >3/6). Protocol details and a description of the population at study inclusion have been published previously (12).

This analysis concerns the baseline data of 987 patients, 473 men (48%) and 514 women (52%), mean age of 77 ± 5 years, mean BMI of 30 ± 5 kg/m², mean waist-to-hip ratio of 0.98 ± 0.09, mean systolic and diastolic blood pressures of 140 ± 19 and 74 ± 11 mmHg, respectively, mean duration of diabetes of 18 ± 11 years, mean HbA_1c level of 7.6 ± 1.3% (60 ± 14 mmol/L), and mean Modification of Diet in Renal Disease score of 67 ± 23 mL/min. Insulin was used by 568 patients (57.5%); 698 of the patients (70.7%) were treated by oral administration of the following drugs: α-glucosidase inhibitors 49 patients (5.0%); biguanides 482 patients (48.8%); dipeptidyl peptidase-4 inhibitors 99 patients (10.0%); glinides 144 patients (14.6%); glitazones 51 patients (7.3%); and sulfonylureas 282 patients (28.6%). Forty-seven patients (4.8%) had received treatment with glucagon-like peptide 1 inhibitors.

The aim was to investigate the relationship between cardiovascular complications and geriatric scale scores. The data collection was primarily based on the patient history and physical examination results. Because of the observational nature of the study, additional systematic testing was not carried out, and some tests were left to the discretion of the investigators according to the French guidelines for diabetes management (13,14).

The physical examination included standardized measurements of waist and hip circumference. Blood pressure was measured with the patient in the supine position after a 5-min rest, and orthostatic hypotension was based on measurements after standing for 1, 3, and 5 min. Patients were considered to have tobacco or alcohol exposure when use was ongoing at study inclusion or had lasted for <5 years.

A geriatric assessment was systematically performed using the following five scales: the Mini Mental State Examination (MMSE), which studies cognition, ranging from 0 to 30 (>24 = normal); the screening part of the Mini Nutritional Assessment (MNA; screening), ranging from 0 to 14 (14 = normal); the ADL scale, ranging from 0 to 6 (6 = independent), and the instrumental ADL (IADL) scale, ranging from 0 to 14 (14 = totally independent), both of which assess autonomy; and the mini-Geriatric Depression Scale (mini-GDS), which evaluates mood, ranging from 0 to 4 (0 = no depression).

Cardiovascular complications were diagnosed through the medical history, physical examination results, and electrocardiogram (ECG), which were performed systematically. Because of the observational nature of the study, complementary examinations were left to the discretion of the investigators, based on results of systematic assessments and according to the French guidelines for diabetes management (14). These included Doppler tests for lower limbs and cerebral vessels, echocardiography, computed tomography, angiography, and tests for silent ischemia (15). All complementary tests had to be agreed to by the patients.

According to results of these clinical and complementary tests, coronary heart disease was classified into three groups (Table 1): myocardial infarction, if any evidence was found through history, ECG, or complementary examinations; angina pectoris, if no evidence was found for infarction and evidence was found through history, ECG, or complementary examinations; and no coronary heart disease otherwise. Heart failure (Table 2) was classified as “left and right” if evidence was found for both left and right heart failure on clinical or complementary examinations. Similarly, univentricular heart failure were classified as either “left” or “right.” Because of the low number of patients with pure right heart failure (10 patients, 1.0%), one group was made for patients with either left or right heart failure. Vascular disease of the lower limbs and of cerebral vessels (Tables 3 and 4) were classified into the following three groups: clinical, when evidence was found; subclinical, when hemodynamic stenosis was found on Doppler tests either performed at inclusion or recorded in the medical history of the patient; and no arterial disease otherwise. Reversible cerebrovascular involvement was based on clinical history and was grouped with subclinical abnormalities of cerebral vessels (Table 4).

Results are presented as the mean ± SD or percentage. Bivariate analyses were performed using the χ² test or the Kruskal-Wallis analysis. Multivariate analyses were performed with a stepwise logistic regression (maximum likelihood ratio), using forward and backward procedures. The variables tested in the multivariate model were those that had a significant association with the complication under study using bivariate analyses. Cardiovascular complications were coded 0 (no complication), 1 (minor), or 2 (major), respectively, using the same classification as that in bivariate analyses, and were grouped as 0 (without complication) versus 1 or 2 (with complication) when needed. Analyses were performed using SAS version 9.2 software (SAS Institute Inc., Cary, NC). Level of significance was set at 0.05.

Of the 987 patients, 536 (54.3%) had at least one of the cardiovascular complications under study. Cognitive disorders (MMSE score ≤24) were found in 144 patients (26.9%) with cardiovascular complications and in 86 patients (19.1%) without complications (P < 0.01). Abnormal nutritional status (screening MNA score <14) was found in 277 patients (51.7%) with cardiovascular complications and in 205 patients (45.5%) without complications (P < 0.05). Impaired activities (ADL score <6) were found in 181 patients (33.8%) with cardiovascular complications and in 77 patients (17.1%) without complications (P < 0.001), and impaired instrumental activities (IADL score <14) in 309 and 206 patients (57.6 and 45.7%), respectively (P < 0.001). Mood disorders (mini-GDS score >0) were found in 130 patients (24.3%) with cardiovascular complications and in 103 patients (22.9%) without complications (not significant).

Coronary insufficiency was observed in 308 patients (Table 1). Echocardiography was performed at study inclusion in 213 patients (21.6%) and showed hypokinesia in 29 patients (13.6% of the tests; 2.9% of the population). No other complementary test was performed. Echocardiography was performed with a similar frequency in patients with and without impaired geriatric scale scores (MMSE scores: 20.8 vs. 22.3%; MNA score: 22.1 vs. 20.7%; ADL score: 22.0 vs. 21.1%; IADL score: 22.2 vs. 21.2%; mini-GDS score: 20.9 vs. 22.1%; difference not significant). The frequency of cognitive disorders in the three groups was alike; the geriatric scores were similar, except for the ADL score, which differed significantly (Table 1). The logistic model successively retained hypercholesterolemia, the ADL score, sex, hypertension, and HbA_1c level as factors associated with coronary insufficiency (70.3% concordance; P < 0.001).

Heart failure was observed in 100 patients (10.1%), including 13 patients (1.3% of patients, 6.1% of tests) in whom heart failure had been diagnosed using echocardiography at study inclusion (Table 2). No other complementary test was performed. Heart failure was associated with the presence of cognitive disorders and with lack of autonomy in ADLs. Multivariate analysis successively found an association between heart failure and hip circumference, age, and HDL cholesterol (70.7% concordance; P < 0.001).

Arterial disease of the lower limbs was observed in 253 patients (25.6%), including 55 (5.6% of patients, 23.4% of tests) of 235 patients (23.8%) with hemodynamic stenosis found on a Doppler test performed at baseline (Table 3). A lower-limb Doppler test was performed with a similar frequency in patients with and without impaired geriatric scale scores (MMSE score 24.6 vs. 23.1%; MNA score 23.0 vs. 24.5%; ADL score 22.6 vs. 24.7%; IADL score 22.9 vs. 24.3%; mini-GDS score 23.9 vs. 23.7%; difference not significant). Arterial disease of the lower limbs was associated with altered scores on the IADL, ADL, and MMSE scales (Table 3). Logistic regression successively individualized the duration of diabetes, the IADL score (P < 0.001), hypertension (P < 0.01), and sex (P < 0.05) as factors associated with vascular disease of the lower limbs (62.8% concordance; P < 0.001).

Cerebrovascular involvement was found in 156 patients, including 45 (4.6% of patients, 17.5% of tests) of 257 patients (26.1%) with hemodynamic stenosis found on a Doppler test performed at baseline (Table 4). A neck artery Doppler test was performed with a similar frequency in patients with and without impaired geriatric scale scores (MMSE score 27.8 vs. 25.8%; MNA score 26.2 vs. 25.9%; ADL score 25.6 vs. 26.3%; IADL score 25.4 vs. 26.7%; mini-GDS score 26.0 vs. 26.2%; difference not significant). Cognitive disorders were more common in patients with cerebrovascular involvement, and the geriatric scale scores were more often distorted, with the exception of the mini-GDS scale score (Table 4). The logistic model successively associated cerebrovascular involvement with the IADL score, sex (P < 0.001), known hypertension (P < 0.01), and ADL score (P < 0.05) (65.6% concordance; P < 0.001).

Over a 1-year period, 987 type 2 diabetic outpatients, all aged ≥70 years and with relatively preserved autonomy, were consecutively included in the prospective GERODIAB cohort (12).

In our observational study, systematic assessments of cardiovascular complications included medical history, clinical examination, and ECG. Other explorations were decided by the investigator, based on the results of systematic assessments, French recommendations (14), and the agreement of the patient to perform the examination. This is likely to underestimate the frequency of complications, especially the silent ones, which has not been screened for previously. However, systematic examinations, including Doppler tests, echocardiography, and screening for silent ischemia, could induce a main selection bias in the population under study. Therefore, examinations were conducted using indications likely to be representative of everyday practice in a quite reliable sample of French elderly type 2 diabetic patients.

Our primary finding was the association between macroangiopathic complications and impaired geriatric scale scores. Similar results have been reported previously, especially regarding the impact on physical function (11,15). Geriatric dysfunctions, and especially cognitive disorders, have been suspected to be associated with poor diabetes control (16–18). Conversely, poor metabolic control and especially hypoglycemia, has been suspected to favor cognitive decline (19,20). However, studies in elderly people with type 2 diabetes remain uncommon, whereas life expectancy and incidence of diabetes are increasing. Therefore, it is now important to analyze the relationships between diabetes complications and geriatric functions in this population. Follow-up studies are especially required in this field. In our study, the relationship between cardiovascular complications and geriatric function is especially interesting, inasmuch as it was supported by multivariate logistic regression, which takes into account other explanatory factors. It suggests that impaired geriatric functions could be independent factors associated with macrovascular diseases. However, in this observational crossover part of the GERODIAB study, logistic regression does not allow the drawing of strong conclusions, especially regarding causal inferences. Thus, our conclusions at baseline remain hypotheses, and should be confirmed by other studies and by follow-up results of the GERODIAB study over 5 years.

These associations suggest that cardiovascular disease may play a role in the genesis of disorders affecting autonomy, cognitive function, nutrition, and mood in elderly diabetic patients (20,21). Heart failure, vascular disease of the lower limbs, stroke sequelae, or coronary artery disease may be the cause of reduced autonomy, worsening of cognitive function, or malnutrition, or may lead to depression. Conversely, the geriatric symptoms can have a prolonged effect on macroangiopathic complications by reducing treatment compliance or increasing the hypoglycemic risk (22). A direct relationship is not certain, and a common mechanisms leading to both macroangiopathy and cognitive, nutritional, autonomic, and/or mood disorders could be involved. This relationship may be the direct consequence of diabetes and risk factors that simultaneously lead to macroangiographic complications and to a combination of more specific geriatric symptoms. It is, however, likely that both of these types of complications influence one another.

Cognitive deficits, as assessed in our study by an MMSE score of ≤24, proved to be more frequent in patients affected by all types of macroangiopathic complications, especially in the event of cerebrovascular involvement. Direct causality between cerebrovascular involvement and cognitive disorders appears obvious.

Malnutrition, the frequency of which was known in these elderly patients, was also more frequent in the presence of cerebrovascular involvement. The potential consequences of motor deficits on feeding cannot be ruled out, but direct action on the appetite centers is possible.

Loss of patient autonomy likewise occurs in a similar manner. The consequences of cerebrovascular involvement are clear in this setting; limitations relative to vascular disease of the lower limbs, and heart failure or coronary insufficiency are also obvious.

The relationship with mood disorders is particularly interesting. More than a direct consequence of an activity deficit or limitation related to cardiovascular complications, it is the psychological impact of these limitations that are pertinent here. The interaction between mood and cognitive disorders is complex. Depression is not rare in early stages of dementia. On the other hand, the MMSE may be underestimated in case of mood disorders.

Few studies have focused on macroangiopathic complications in the elderly and their relationship with geriatric parameters. This study, which will have a 5-year follow-up period, already shows in its initial evaluation the significant association between macroangiopathic complications and geriatric syndromes. This fact supports systematic evaluation of these patients based both on the diabetes as well as the geriatric functions. An early systematic global assessment of elderly type 2 diabetic patients could be a simple and inexpensive approach. This step should improve the identification of these patients, so that the objectives and treatment can be adapted and their quality of life optimized.

The authors thank D. Dubois, C. Hilbert, A. Ourliac, and D. Boichut from Umanis for data collection, management, and analyses. The authors also thank J. Klain-Ratziu for contribution to the translation.

Funding. This work was supported by a French grant for public hospitals (PHRC) and by a grant from the French-speaking Society for Diabetes.

Duality of Interest. This study was also supported by grants from Novo Nordisk and Merck-Serono. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. B.B. researched the data and wrote the manuscript. J.D. and C.V. researched the data and reviewed the manuscript. J.-P.L.F. contributed to the data analyses and reviewed the manuscript. J.-P.L.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Appendix The participating members of the Scientific Committee and Study Investigators of the SFD/SFGG Intergroup are B. Bauduceau, J.F. Blicklé, I. Bourdel-Marchasson, T. Constans, J. Doucet, A. Fagot-Campagna, V. Lassmann-Vague, P. Lecomte, D. Tessier, C. Verny, U. Vischer, H. Affres, M. Alix, F. Archambeaud, Z. Barrou, B. Bauduceau, P. Beau, S. Beltran, C. Benoit, J.-P. Beressi, F. Bernachon, C. Berne, G. Blaimont, J.-F. Blickle, M. Boda-Buccino, J. Bohatier, P. Böhme, L. Bordier, K. Bouchou, B. Bouillet, F. Bouilloud, R. Bouix, E. Boulanger, I. Bourdel-Marchasson, C. Bourgon, E. Bourrinet, P. Brocker, I. Bruckert, C. Capet, C. Carette, B. Cariou, A. Carreau, C. Chaillou Vaurie, S. Chamouni, C. Ciangura, C. Collet-Gaudillat, M.-E. Combes-Moukhovsky, T. Constans, M. Cordonnier, A. Cuperlier, D. Dambre, J. D’avigneau, P. De Botton, V. Degros, F. Delamarre-Damier, S. Denat, F. Desbiez, B. Deumier, F. Dorey, J. Doucet, E. Dresco, A. Drutel, E. Du Rosel De Saint Germain, D. Dubois-Laforgue, B. Duly-Bouhanick, O. Dupuy, L. Dusselier, S. Faucher-Kareche, S. Fendri, P. Fontaine, S. Galinat, H. Gin, F. Glaise, T. Godeau, B. Gonzalez, I. Got, B. Guerci, P.-J. Guillausseau, S. Hadjadj, Y. Hadjali, M. Halbron, S. Halimi, C. Halter, H. Hanaire, V. Hardy, A. Hartemann-Heurtier, J.-P. Haulot, F. Hequet, M. Issa-Sayegh, P. Jan, N. Jeandidier, H. Joseph-Henri, I. Julier, V. Kerlan, T. Kharitonnoff, M. Ladsous, L. Lahaxe, M.-P. Lamaraud, E. Lassenne, J.-M. Lecerf, P. Lecomte, I. Leroux, S. Lesven, M. Levy, S. Lopez, F. Makiza, P. Manckoundia, C. Marquis Pomeau, M. Matta, H. Mayaudon, S. Micheli, R. Mira, F. Monnier, H. Mosnier-Pudar, N. Neri, I. Normand, M. Paccalin, C. Pagu, D. Paris, A. Penfornis, J.-L. Perie, J.-M. Petit, G. Petit Aubert, B. Pichot-Duclos, L. Pivois, M. Popelier, G. Poulingue, M. Priner, Dr V. Quipourt, M. Rasamisoa, J.-L. Richard, V. Rigalleau, N. Roudat, C. Sanz, J.-M. Serot, D. Sifi, S. Sirvain, A. Slimani, E. Sonnet, C. Sosset, A. Soualah, A. Stroea, I. Tauveron, J. Timsit, M. Tschudnowsky, A. Vambergue, O. Verier-Mine, C. Verny, and M. Virally.