by
Federico Cacciapuoti MD.
Assistant Professor of Internal Medicine and Geriatry
Faculty of Medicine, Second University of Naples, Italy.

Introduction

Advancing age is often associated with Insulin Resistance (IR). NHANES III evidenced that metabolic syndrome is predominant in further 44% of U.S. individuals older than 50 years (1). The progressive increase of IR induces an Impaired Glucose Tolerance (IGT). The prevalence of IGT among adults varies between 3 and 10% in European population and 20% in North American people.
Although IGT is not associated with diabetes-specific complications, it does increase the risk of developing both type 2 diabetes and cardiovascular disease (2). IR that may be found in ageing is favoured by obesity and physical inactivity (3-5) but it is often present without these two age-related conditions. Some alterations occurring with advanced age may contribute to the impairment of insulin secretion and action, including physical fitness, hormonal changes (growth hormone, insulin-like factors, sex steroids, etc.), decline in muscle mass, increased muscle weakness and fatigability, prevalence of abdominal obesity (6). IR so occurring is responsible for hyperglycaemia that is particularly high and lasting in the post-prandial period, in these aged persons with IR.

Effects of hyperglycemia
It is known that hyperglycaemia results in the over-production of reactive oxygen species (ROS) that cause oxidative stress (7). This process covers a central role in the development of micro and macrovascular complications hyperglycemia-dependent, through endothelial dysfunction and reduction in flow mediated vasodilation (8-10). Another major pathway of oxidative stress-inducing vascular damage is mediated through the depletive effects of the superoxide anion on nitric oxide (NO). In addition, several evidences support a direct role of hyperglycaemia in favoring a nitrotyrosine overgeneration (11), responsible for endothelial dysfunction.

Esposito et al. also found that some indicators of inflammation, such as cytokines, interleukin-6 and tumor necrosis factor- , increase during hyperglycaemia (12). Finally, oxidative stress secondary to hyperglycaemia has been implicated in the up-regulation of soluble adhesion molecules (13) and in favouring the activation of the coagulation processes means by platelet activation and thrombin generation (14). Thus, elevation of glucose levels causes inflammation, oxidative stress, endothelial dysfunction, vasoconstriction and hypercoagulation responsible for cardiovascular damage.

Postprandial hyperglycaemia
The hyperglycaemic "spikes" happening after meal in the elderly are accentuated for the reasons before expressed and may be relevant for the atherosclerotic process and cardiovascular complications. From the epidemiological point of view, the Honolulu Heart Study and, more recently, the DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) (15.16) have shown that the serum glucose level verifying during 2 hours after meal is a powerful predictor of cardiovascular risk.

The Diabetes Intervention Study illustrates that postprandial hyperglycaemia predicts acute myocardial infarction in type 2 diabetic subjects (17). Another study shown that medio-intimal carotid thickening is correlated with postprandial glucose serum levels (18). A close correlation between glucose serum levels and cardiovascular events even in nondiabetic subjects was also described (19). This consists of the evidence that in normal subjects, an acute increase of glycaemia significantly prolongs Q-T (20). All these evidences confirm that postprandial hyperglycaemia (especially associated with glucose intolerance) induces an increased risk of cardiovascular events. The profile of postprandial hyperglycaemia is determined by many factors, including the timing, quantity and composition of the meal, and the secretion of insulin (reduced in the elderly) and inhibition of glucagon secretion.

STOP-NIDDM Study
In STOP-NIDDM (Study TO Prevent Non Insulin Dependent Diabetes Mellitus) trial, some authors have shown in subjects with IGT, acarbose (an -glucosidase inhibitor that specifically reduces postprandial hyperglycemia) is able to prevent or delay the development of type 2 diabetes and some cardiovascular complications (21). The drug reduces the rate of carbohydrate absorption, by inhibiting the enzymatic conversion of oligosaccharides to monosaccharides and disaccharides (22). The compound was taken at each meal assumption, three times a day, at dose of 100 mg. per os .

The subjects were examined every 3 months and every 6 months, for a median follow-up time of 3.9 years. The use of acarbose in individuals with IGT is associated not only with a 36% reduction in the risk in progression to diabetes mellitus but also with a reduction of 34% of systolic and diastolic blood pressure and a 49% risk reduction in cardiovascular events. In addition, in a sub-study, acarbose treatment was associated with a significant decrease in the progression of carotid intima-media thickness, an accepted surrogate for atherosclerosis (23). Furthermore, a meta-analysis of seven double-blind placebo-controlled, randomized trials has shown that intervention with acarbose significantly improves triglyceride levels, body weight and waist circumference and reduces the MI risk (24). These observations suggest that prevention of post-prandial hyperglycaemia with acarbose seems to be a promising therapeutic strategy for reducing the increased risk of diabetes, systemic hypertension.

Dyslipidemia and cardiovascular disease both in patients with IR and in those with clinical diabetes mellitus.
The mechanism of action of acarbose avoids several common adverse events associated with other anti-diabetes therapies and, consequently, acarbose has few contraindications (25). The drug is poorly absorbed into the bloodstream and the risk of any toxic reaction is very low (26). As consequence of its mode of action on the carbohydrates, flatulence, meteorism and diaorrea are frequently reported in the first week after starting acarbose treatment.

HEART2D Trial
But, the recent HEART2D (Hyperglycemia and its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2Diabetes Mellitus) trial did not show any beneficial effect of treating post-prandial hyperglycemia in reducing cardiovascular disease in diabetic patients at very high risk for more cardiovascular events (27). Nevetheless, some criticisms can be done:
1) The control of postprandial hyperglycaemia was performed insulin therapy, without the use of acarbose.

2) All patients were enrolled within 21 days of hospital admission for a recent acute myocardial infarction (AMI), i.e. the treatment of post-prandial hyperglycemia was started when the cardiovascular disease was already present.

3) Patients were very well treated with other drugs for cardiovascular disease at beginning of the study (for the presence of recent AMI).

Conclusive remarks
To reduce the atherosclerosis progression and the frequence of cardiovascular events in the elderly favoured by the hyperglycaemic post-prandial "spikes", together with the physical activity and the reduction of food intake, we suggest a daily acarbose therapy. Acarbose treatment could be performed in individuals aged for 65 to 75-80 years, without ouvert diabetes mellitus too, after performing an Oral Glucose Tolerance Test (OGTT) showing a condition of IGT (defined as a 2 h glucose level>/=140 mg/dl, but<200 mg/dl by OGTT, and a fasting blood glucose not in the diabetic range) (28). The drug should be given per os, at dose of 25 mg b.i.d. or t.i.d. This treatment indefinitely lasted and performed in accordance with OGTT changes, should reduce the rapidity and the seriousness of the atherosclerosclerotic processes and the frequence of some cardiovascular acute events characterizing the older aged subjects, expecially those with IR.

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Address for correspondence:

Prof. Federico Cacciapuoti
Cattedra di Medicina Interna e Geriatria
Facoltà di Medicina e Chirurgia
Seconda Università degli Studi di Napoli
Piazza L. Miraglia, 2
80138-Napoli-
phone: 081/5665022