Rationale for a metabolic intervention in obese patients with coronary heart disease

Ioana Holban, P. Goldenberg, Paris, France
Correspondence: P. Goldenberg, Pharm D/ I. Holban, MD, 31 rue du Pont,92200 Neuilly s/ Seine, France

Abstract

Obesity and diabetes are common associated risk factors that contribute to increased cardiovascular mortality. Their prevalence is increased in patients with coronary artery disease; coexisting changes in cardiac metabolism worsen the consequences of myocardial ischemia. Pharmacologic manipulation of cardiac metabolism has proved to be a rational approach to patients with
coronary heart disease and diabetes, and/or obesity. This is evidenced by the clinical benefits that can be derived from the use of trimetazidine, the first 3-ketoacyl-CoA-thiolase inhibitor, a
metabolic anti-ischemic agent that optimizes cardiac metabolism secondary to a reduction in fatty acid oxidation. n Heart Metab. 2002;17:26–30.

Keywords: Obesity, coronary artery disease, trimetazidine, cardiac metabolism

Introduction
Obesity is a complex, multifactorial, chronic disease characterized by excess body fat resulting from an imbalance between energy expenditure and caloric intake. The causes of this imbalance appear to be physiological, metabolic, and genetic, as well as environmental, cultural, and social.
Overweight and obesity are recognized as a major cause of the increase in serious and life-threatening diseases, in particular excessive cardiovascular mortality [1]. The relationship between body mass index and mortality is curvilinear [2, 3].
The primary comorbidities of obesity are type 2 diabetes, cardiovascular diseases, hypertension, reproductive disorders, certain cancers, and respiratory diseases.
Patients with intra-abdominal fat accumulation (android obesity) tend to have a cluster of metabolic abnormalities known as the metabolic syndrome, or syndrome X [4]. A combination of insulin resistance, hyperinsulinemia, dyslipidemia, and essential hypertension is the hallmark of the metabolic syndrome [5, 6]. All are major risk factors for most coronary diseases, and a correlation has been shown between android obesity, elevated risk for coronary artery disease, and mortality [5, 7, 8].

Obesity, insulin resistance, dyslipidemia, and coronary heart disease: a fatal combination?
Although genetic factors clearly play a role in the development of insulin resistance or type 2 diabetes, obesity is the most potent environmental risk factor for type 2 diabetes [9]. Both obesity and diabetes are increasing at an alarming rate among the general population; the prevalence of diabetes is 3.8 times higher in overweight than in normal subjects 20 to 45 years of age [10].
Type 2 diabetes and obesity are associated with a cluster of atherogenic risk factors: weight gain and visceral adiposity give rise to an increased insulin requirement which may lead to hyperinsulinemia and, ultimately, diabetes [5, 11–13]. Several factors may contribute to the development of insulin resistance in the obese patient, including abnormalities in free fatty acids, hormone signaling, and genetic polymorphisms [14, 15]. The increased levels of plasma free fatty acids and steroid hormone abnormalities observed in obese patients may modify insulin sensitivity in the peripheral tissues [16].
Hypertriglyceridemia in association with hypercholesterolemia is common in obesity and type 2 diabetes, exacerbating a genetic predisposition to coronary artery disease [8]. The underlying metabolic abnormalities behind dyslipidemia are insulin resistance and hyperinsulinemia. Hypertriglyceridemia further leads to an increase in low-density lipoprotein cholesterol; a decrease in high-density lipoprotein cholesterol is also commonly observed [17].
Primary cardiovascular risk factors such as lack of physical exercise, insulin resistance (and associated hyperinsulinemia), dyslipidemia, and type 2 diabetes are present in the obese patient [18]. All those risk factors, together with the increased demand that obesity imposes on the heart to supply blood to the peripheral organs, explain the raised prevalence of cardiovascular disease including coronary artery disease and heart attacks in obese patients (Figure 1) [11].


Figure 1. Interrelations between obesity, cardiovascular risk factors, and IHD. IHD, Ischemic heart disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Trimetazidine: a rational choice in coronary patients at increased cardiovascular risk
Changes in cardiac metabolism during ischemia represent an inevitable step in the ischemic cascade, which is exacerbated in obese patients (Figure 2).


Figure 2. The ischemic cascade: from myocardial ischemia to angina.

Concomitant diabetes present in obese patients has a negative impact on myocardial metabolism: diabetes impairs glycolysis, pyruvate oxidation, and lactate uptake, and creates a greater dependency on fatty acids (which are in excess in the obese patient) as a source of acetyl-CoA. It contributes to the increase in ischemic symptoms since more oxygen is required to produce each molecule of ATP than via the carbohydrate pathway. Shifting cardiac metabolism away from fatty acid oxidation to glucose oxidation can significantly improve cardiac efficiency (cardiac work/oxygen consumed) [19]. In this context, manipulation of cardiac metabolism that results in a switch to optimal substrate utilization is particularly appropriate.
Thus, trimetazidine, with its specific metabolic mechanism of action, is a treatment of choice for obese diabetic patients with coronary heart disease. Trimetazidine is a metabolic anti-ischemic agent known to optimize cardiac energy metabolism without causing any adverse hemodynamic effects. It acts by inhibiting long-chain 3-ketoacyl-CoA-thiolase, which results in partial inhibition of fatty acid oxidation and stimulation of glucose oxidation [20]. This shift in substrate preference leads to a 12% improvement in ATP production, limits cell acidosis, and preserves the contractile function of the heart [21].
The anti-ischemic and cardioprotective effect of trimetazidine translates into clinical benefits. The first-line antianginal efficacy of trimetazidine has been confirmed in monotherapy versus placebo [22] and in comparison with reference drugs [23, 24]. Trimetazidine has also proven additive value in combination with conventional agents in patients resistant to b-blockers [25, 26] and calcium antagonists [27, 28].
Trimetazidine has been shown to be particularly suitable for diabetic patients since the diabetic heart has an increased sensitivity to ischemia due to a greater reliance on fatty acid oxidation. This was evidenced in a subanalysis of anti-ischemic efficacy and tolerability from a multicenter study. Trimetazidine 20 mg tid improved cardiac markers in 50 diabetic coronary patients after 1 month of therapy [29]. Ergometric parameters, such as exercise duration (Figure 3), were significantly enhanced.

Figure 3. Effect of trimetazidine on exercise duration in diabetic patients with angina.

Another trial assessed the short- and long-term efficacy of trimetazidine in coronary patients with diabetes and ischemic dilated cardiomyopathy in addition to standard therapy. Results demonstrated a significant improvement in symptoms, left ventricular function, glucose metabolism, and endothelial function in comparison with placebo [30].
Taken together, these data strongly suggest that pharmacological manipulation of cardiac metabolism with a metabolic anti-ischemic agent such as trimetazidine is a sound choice in coronary patients with concomitant risk factors such as diabetes and obesity.





REFERENCES

1: Int J Obes Relat Metab Disord 1998 Jan;22(1):39-47 Related Articles,

Overweight and obesity in the United States: prevalence and trends, 1960-1994.

Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL.

National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville MD 20782, USA.

OBJECTIVE: To describe the prevalence of, and trends in, overweight and obesity in the US population using standardized international definitions. DESIGN: Successive cross-sectional nationally representative surveys, including the National Health Examination Survey (NHES I; 1960-62) and the National Health and Nutrition Examination Surveys (NHANES I: 1971-1974; NHANES II: 1976-1980; NHANES III: 1988-94). Body mass index (BMI:kg/m2) was calculated from measured weight and height. Overweight and obesity were defined as follows: Overweight (BMI > or = 25.0); pre-obese (BMI 25.0-29.9), class I obesity (BMI 30.0-34.9), class II obesity (BMI 35.0-39.9), and class III obesity (BMI > or = 40.0). RESULTS: For men and women aged 20-74 y, the age-adjusted prevalence of BMI 25.0-29.9 showed little or no increase over time (NHES I: 30.5%, NHANES I: 32.0%, NHANES II: 31.5% and NHANES III: 32.0%) but the prevalence of obesity (BMI > or = 30.0) showed a large increase between NHANES II and NHANES III (NHES I: 12.8%; NHANES I, 14.1%; NHANES II, 14.5% and NHANES III, 22.5%). Trends were generally similar for all age, gender and race-ethnic groups. The crude prevalence of overweight and obesity (BMI >> 25.0) for age > or = 20 y was 59.4% for men, 50.7% for women and 54.9% overall. The prevalence of class III obesity (BMI > or = 40.0) exceeded 10% for non-Hispanic black women aged 40-59 y. CONCLUSIONS: Between 1976-80 and 1988-94, the prevalence of obesity (BMI > or= 30.0) increased markedly in the US. These findings are in agreement with trends seen elsewhere in the world. Use of standardized definitions facilitates international comparisons.

PMID: 9481598 [PubMed - indexed for MEDLINE]

 2. National Institutes of Health Consensus Development Panel on the Health Implications of Obesity. Health implications of obesity: National Institutes of Health Consensus Development Conference Statement. Ann Intern Med. 1985;103:1073–1077.

3: JAMA 1993 Dec 15;270(23):2823-8 Related Articles,

Comment in:


Body weight and mortality. A 27-year follow-up of middle-aged men.

Lee IM, Manson JE, Hennekens CH, Paffenbarger RS Jr.

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115.

OBJECTIVE--To investigate the nature of the relation between body weight and all-cause mortality. DESIGN--Prospective cohort study, following up men from 1962 or 1966 (1962/1966) through 1988. SETTING/PARTICIPANTS--Harvard University alumni with a mean age of 46.6 years in 1962/1966 and without self-reported, physician-diagnosed coronary heart disease, stroke, or cancer, who completed questionnaires on weight, height, cigarette smoking habit, and physical activity (n = 19,297). We calculated body mass index (weight in kilograms divided by the square of height in meters) using self-reported measures. MAIN OUTCOME MEASURE--All-cause mortality (4370 deaths). RESULTS--In multivariate analysis adjusting for age, cigarette smoking habit, and physical activity, we found a J-shaped relation between body mass index and mortality. Relative risks of dying for men with a body mass index of less than 22.5, 22.5 to less than 23.5, 23.5 to less than 24.5, 24.5 to less than 26.0, and 26.0 or greater were 1.00 (referent), 0.99 (95% confidence interval, 0.89 to 1.20), 0.95 (0.87 to 1.05), 1.01 (0.91 to 1.10), and 1.18 (1.08 to 1.28), respectively (P for linear trend = .0008). Among current smokers, the relation between body mass index and mortality was U-shaped, with lowest risk of death at a body mass index of 23.5 to less than 24.5. During early follow-up (1962/1966 through 1974), we also observed a U-shaped curve, this time with lowest mortality risk at a body mass index of 24.5 to less than 26.0. To minimize confounding by cigarette smoking and bias from antecedent disease and early mortality, we conducted analysis only among never smokers and omitted the first 5 years of follow-up (510 deaths). The corresponding relative risks from this analysis, adjusted for age and physical activity, were 1.00, 1.23 (95% confidence interval, 0.90 to 1.67), 1.06 (0.80 to 1.42), 1.27 (0.96 to 1.68), and 1.67 (1.29 to 2.17), respectively (P for linear trend = .0001). CONCLUSIONS--In these prospective data, body weight and mortality were directly related. After accounting for confounding by cigarette smoking and bias resulting from illness-related weight loss or inappropriate control for the biologic effects of obesity, we found no evidence of excess mortality among lean men. Indeed, lowest mortality was observed among men weighing, on average, 20% below the US average for men of comparable age and height.

PMID: 8133621 [PubMed - indexed for MEDLINE]

 
4: J Med 2001;32(5-6):283-300 Related Articles,

Metabolic syndrome X: a comprehensive review of the pathophysiology and recommended therapy.

Lopez-Candales A.

Cardiovascular Institute, University of Pittsburgh, Pennsylvania, USA. lopezcandalesa@msx.upmc.edu

Diabetes mellitus is associated with a markedly increase prevalence of coronary artery disease, found to be as high as 55% (Lyons, 1993). The metabolic syndrome X, a multifaceted clinical entity produced by genetic, hormonal and lifestyle factors which occurs frequently in the general population, has been associated as an end point in patients with diabetes (Timar, Sestier et al., 2000). New data suggests that a clustering of truncal obesity, glucose intolerance or non-insulin dependent diabetes mellitus, dyslipidemia and essential hypertension are key components of this metabolic syndrome X (Timar, Sestier et al., 2000). In fact, the metabolic syndrome X has been shown to precede frank diabetes in a substantial number of patients; hence similar multiple cardiac risk factors will be found in this population. Thus, primary care providers should identify patients at an early stage so that appropriate treatment can be readily instituted. The goal of this review is to summarize criteria for diagnosis of patients with the metabolic syndrome X and therapeutic targets of each individual component is analyzed in a attempt to reduce cardiovascular events and improve clinical outcome based on the available clinical data.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11958275 [PubMed - indexed for MEDLINE]

 
5: Nutrition 1993 Sep-Oct;9(5):452-9 Related Articles,

Abdominal obesity as important component of insulin-resistance syndrome.

Despres JP.

Lipid Research Center, Laval University Medical Research Center, CHUL, Quebec, Canada.

The regional distribution of body fat has been identified as a significant risk factor for the development of noninsulin-dependent diabetes mellitus and cardiovascular disease (CVD). Several studies that have investigated the potential associations between topographic features of adipose tissue and indices reflecting carbohydrate and lipid metabolism have reported significant associations between abdominal fat deposition and metabolic complications. The development of computed tomography as a means to precisely measure the amount of subcutaneous and deep adipose tissue at any site of the body has shown that determination of the level of visceral adipose tissue is a critical measurement to perform in the assessment of the health hazards of obesity. Studies that we have conducted in premenopausal women have clearly shown that the level of visceral adipose tissue is the best correlate of lipoprotein ratios used to estimate the risk of CVD. We have also reported that a high level of visceral adipose tissue is associated with a deterioration of glucose tolerance and that the relationship between visceral fat deposition and glucose tolerance remains significant after controlling for the level of total-body fat. Because significant interrelationships were observed between abdominal visceral obesity, insulin resistance, and dyslipoproteinemias in obese women, it is suggested that visceral obesity is an important component of the insulin-resistance syndrome (syndrome X) that has been previously described. This cluster of morphological, hormonal, and metabolic alterations observed in abdominal obesity may have substantial implications for the treatment of this condition.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 8286886 [PubMed - indexed for MEDLINE]

 
6: Ann N Y Acad Sci 1995 Dec 29;771:665-76 Related Articles,

Hypercortisolism and obesity.

Peeke PM, Chrousos GP.

Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892, USA.

Obesity is a multifactorial heterogenous condition. The location of excess fat on the body determines the risk of morbidity and mortality for significant disease. Visceral, or intraabdominal, fat is the fat depot most highly associated with illness and death from cardiocerebrovascular disease and diabetes. Visceral fat is also associated with a quartet of metabolic disturbances. Referred to as the metabolic syndrome, these abnormalities include hypertension, hyperlipidemia, hyperinsulinemia, and insulin resistance. The metabolic syndrome is also present in Cushing's syndrome, which is characterized by primary hypercortisolism as well as profound visceral adiposity and obesity. The interrelationship between hyperactivation or hypersensitivity of the stress axis and disease can be elucidated by an understanding of the effect of excess glucocorticoids upon energy storage and metabolism. The complex interactions of the stress axis upon the growth and reproductive axes, as well as upon the adipose tissue, suggest that chronic stress, whether psychological and/or physical, exerts an intense effect upon body composition, which, in turn, significantly affects the longevity and survival of the organism.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 8597440 [PubMed - indexed for MEDLINE]

 
7: Ann Intern Med 1993 Oct 1;119(7 Pt 2):655-60 Related Articles,

Medical hazards of obesity.

Pi-Sunyer FX.

St. Luke's-Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons, New York, New York.

The medical hazards of obesity are discussed. Risks include insulin resistance, diabetes mellitus, hypertriglyceridemia, decreased levels of high-density lipoprotein cholesterol, and increased levels of low-density lipoprotein cholesterol. Obesity is also associated with gallbladder disease and some forms of cancer as well as sleep apnea, chronic hypoxia and hypercapnia, and degenerative joint disease. Obesity is an independent risk factor for death from coronary heart disease. A central distribution of body fat enhances the risk for most of these conditions.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 8363192 [PubMed - indexed for MEDLINE]

 
8: Baillieres Clin Endocrinol Metab 1994 Jul;8(3):629-60 Related Articles,

Dyslipidaemia and obesity.

Despres JP.

Lipid Research Center, CHUL Research Center, Ste-Foy, Quebec, Canada.

Obesity is frequently associated with a dyslipidaemic state. Several metabolic and epidemiological studies published in the 1980s have, however, emphasized the importance of considering the regional distribution of body fat in the assessment of the health hazards of obesity. The development of imaging techniques such as computed tomography has also allowed it to be established that the fat located in the abdominal cavity, i.e. the visceral adipose tissue, was the critical correlate of the metabolic complications found in abdominal obesity which include insulin resistance and hyperinsulinaemia, glucose intolerance, hypertriglyceridaemia, hypoalphalipoproteinaemia and increased concentrations of dense LDL particles. Furthermore, since several genes are involved in the regulation of plasma lipoprotein-lipid levels and they have been reported to show polymorphism, visceral obesity should be considered as a permissive factor that exacerbates an individual's susceptibility to dyslipidaemia and premature coronary heart disease rather than a primary regulator of the dyslipidaemic state observed in visceral obese patients. Finally, as insulin resistance and the level of visceral adipose tissue are two main correlates of the dyslipidaemic state which characterizes abdominal obesity, treatment should be aimed at reducing visceral fat and improving insulin sensitivity. Prospective studies are clearly warranted to evaluate the potential benefits of such interventions on the incidence of coronary heart disease.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 7980350 [PubMed - indexed for MEDLINE]

 
9: Med Clin North Am 1989 Jan;73(1):111-38 Related Articles,

Health risks of obesity.

Kissebah AH, Freedman DS, Peiris AN.

Division of Endocrinology, Medical College of Wisconsin, Milwaukee.

Evidence implicating obesity as a risk-factor disease is critically reviewed. Possible reasons for the many conflicting findings are addressed. The classification of obesity, based upon the site of body fat distribution, and possible biologic mechanisms associating regional adiposity with morbidity, are discussed.

Publication Types:
  • Review
  • Review, Academic


PMID: 2643000 [PubMed - indexed for MEDLINE]

 
10: Ann Intern Med 1985 Dec;103(6 ( Pt 2)):983-8 Related Articles,

Health implications of overweight and obesity in the United States.

Van Itallie TB.

The second National Health and Nutrition Examination Survey found that 26% of U.S. adults, or about 34 million people aged 20 to 75 years, are overweight. The survey used a body mass index of 27.8 kg/m2 or greater for men and 27.3 or greater for women to define overweight. Prevalence of overweight increases with advancing age and is generally much higher among black women than among white women. Women below the poverty line have a much higher prevalence of overweight between ages 25 and 55 years than women above the poverty line. Multivariate analysis indicates that for women race and poverty status are independent predictors of overweight. Hypertension, hypercholesterolemia, and diabetes are commoner in overweight persons than in persons who are not overweight. The relative risk of hypertension, hypercholesterolemia, and diabetes is greater in overweight adults aged 20 to 45 years than it is in overweight persons aged 45 to 75 years. This observation is consonant with mortality data, suggesting that being overweight during early adult life is more dangerous than a similar degree of overweight in later adult life.

PMID: 4062130 [PubMed - indexed for MEDLINE]
 
11: Am J Clin Nutr 1992 Feb;55(2 Suppl):488S-494S Related Articles,

Pathophysiology of obesity.

Bray GA.

Pennington Biomedical Research Center, Baton Rouge, LA 70808.

Individuals weighing greater than 100 kg represent a small fraction of the population and yet pose a major health risk to themselves. It is proposed that individuals be classified according to their body mass index (BMI). Class 0 individuals have a BMI of 20-25 kg/m2 and are not obese; Class I individuals have a BMI of 25-30 kg/m2 and are at low risk from their obesity; Class II individuals have a BMI of 30-35 kg/m2 and have moderate risk; Class III individuals have a BMI of 35-40 kg/m2 and have high risk associated with their obesity; Class IV individuals have a BMI of greater than 40 kg/m2 and are at very high risk for illness. Class IV is the primary group for surgical consideration. The pathophysiologic consequences of excess weight result in large part from increased food intake and/or decreased physical activity. Individuals in Class IV have additional problems related to their weight, including cardiomyopathy, Pickwickian/sleep apnea syndrome, pituitary/gonadal dysfunction, acanthosis nigricans, and significant osteoarthritis.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 1733117 [PubMed - indexed for MEDLINE]

 
12: Am J Geriatr Cardiol 2002 Mar-Apr;11(2):119-23,125 Related Articles,

Obesity, diabetes, and risk of cardiovascular disease in the elderly.

Wilson PW, Kannel WB.

Department of Medicine, Boston University Medical School, Boston, MA 02118, USA. pwilson@bu.edu

There is an age-related increase in total body fat and visceral adiposity until age 65 years that often is accompanied by diabetes or impaired glucose tolerance. The prevalence of type 2 diabetes increases progressively with age, peaking at 16.5% in men and 12.8% in women at age 75-84 years. Over age 65, diabetes or glucose intolerance was present in 30%-40% of Framingham Study subjects. There has been an alarming increase, of epidemic proportions, in both obesity and diabetes in the general population. Type 2 diabetes and obesity are both associated with a clustering of atherogenic risk factors, and when three or more are present it generally signifies an insulin resistance syndrome. This is promoted by weight gain and visceral adiposity. The risk of macrovascular disease is increased before glucose levels reach the diagnostic threshold for "diabetes," and 25% of newly diagnosed diabetics already have overt cardiovascular disease. In the Framingham Study, increased risk of cardiovascular disease was two-fold in men and three-fold in women, eliminating the female advantage over men for all outcomes except stroke. Coronary disease is the most common and lethal sequela, and unrecognized myocardial infarctions are three times more common in diabetic than nondiabetic men. Following a myocardial infarction, diabetes imposes a high rate of recurrence, heart failure, and death, more so in women than men. The risk of cardiovascular sequelae in diabetics is variable, the majority of events occurring in those with two or more additional risk factors. Because of the variable risk of cardiovascular disease in either the diabetic or obese person, risk stratification is necessary to determine the hazard of impending cardiovascular disease. This is readily accomplished with Framingham cardiovascular risk formulations. For persons with diabetes or obesity, the chief goal is to avoid the common cardiovascular sequelae. Comprehensive care should include not only normalization of the blood sugar, but also weight reduction, dietary fat restriction, strict blood pressure and lipid control, exercise, and avoidance of tobacco. Trial data indicate that preventive measures benefit obese diabetics even more than nondiabetics. (c)2002 CVRR, Inc.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11872970 [PubMed - indexed for MEDLINE]

 
13: Exp Clin Endocrinol Diabetes 2001;109(Suppl 2):S135-S148 Related Articles,
Click here to read 
Insulin resistance: definition and consequences.

Lebovitz HE.

State University of New York Health Science Center at Brooklyn, U.S.A.

Summary:Insulin resistance is defined clinically as the inability of a known quanity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin action is the consequence of insulin binding to its plasma membrane receptor and is transmitted through the cell by a series of protein-protein interactions. Two major cascades of protein-protein interactions mediate intracellular insulin action: one pathway is involved in regulating intermediary metabolism and the other plays a role in controlling growth processes and mitoses. The regulation of these two distinct pathways can be dissociated. Indeed, some data suggest that the pathway regulating intermediary metabolism is diminished in type 2 diabetes while that regulating growth processes and mitoses is normal. - Several mechanisms have been proposed as possible causes underlying the development of insulin resistance and the insulin resistance syndrome. These include: (1) genetic abnormalities of one or more proteins of the insulin action cascade (2) fetal malnutrition (3) increases in visceral adiposity. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome". This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance. - In this context, we need to consider whether insulin resistance should be defined as a disease entity which needs to be diagnosed and treated with specific drugs to improve insulin action.

PMID: 11723552 [PubMed - as supplied by publisher]
 
14: N Engl J Med 1997 Aug 28;337(9):581-8 Related Articles,

Erratum in:
  • N Engl J Med 1997 Dec 11;337(24):1783


Comment in:

Click here to read 
Valvular heart disease associated with fenfluramine-phentermine.

Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV.

Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.

BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

PMID: 9271479 [PubMed - indexed for MEDLINE]

 
15: Can J Diet Pract Res 2002 Spring;63(1):20-32 Related Articles,

Comment in:


Insulin resistance: concepts, controversies, and the role of nutrition.

Sievenpiper JL, Jenkins AL, Whitham DL, Vuksan V.

Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON.

Insulin resistance is a prevalent condition, in which insulin loses its normal physiological action. Since people were first classified as insulin resistant over 60 years ago, one of the main discoveries has been that insulin resistance clusters with other risk factors such as obesity, elevated triglycerides, and low high-density lipoprotein cholesterol, increasing cardiovascular disease risk. Although insulin resistance appears to manifest first in the periphery and then in the liver, other sites, such as the brain and the pancreatic &b.beta-cell, may play pathogenic roles. Factors contributing to insulin resistance at these sites include perturbations in free fatty acids, glucose, and hormone-signalling, some of which may be linked to various genetic polymorphisms. Appropriate nutritional treatment for insulin resistance is controversial. Two main approaches are drawn from diabetes recommendations: i) a high-carbohydrate, low-fat, high-fibre diet emphasizing low glycemic-index foods and ii) sharing calories between monounsaturated fat and complex carbohydrate at the expense of saturated fat. Recent interest in insulin resistance has prompted the development of new guidelines. Promising data have also emerged, showing that a high-carbohydrate, high-fibre, low-fat diet plus exercise programs maintained through intensive counselling can decrease diabetes risk by over 40%. Additional research is required to confirm the sustainability of this approach and sort out the determinants of insulin resistance so that more effective nutritional interventions will result.

Publication Types:

  • Review
  • Review, Tutorial


PMID: 11916461 [PubMed - indexed for MEDLINE]

 
16: Metabolism 1995 Feb;44(2 Suppl 2):38-41 Related Articles,

Neuroendocrine abnormalities in human obesity.

Bjorntorp P.

Department of Heart and Lung Diseases, University of Goteborg, Sweden.

Recent research has indicated that visceral obesity is associated with multiple endocrine disturbances. Insulin resistance, as well as visceral fat accumulation, may be consequences of these abnormalities. The complex endocrine aberrations are probably of central origin, and suggest a neuroendocrine background with a "hypothalamic arousal" syndrome. Such a syndrome has been found after excess alcohol intake, tobacco smoking, and certain types of stress reactions. Subjects with visceral obesity might be characterized by a high prevalence of such factors, although only indirect evidence is available for the stress component, maybe caused by a poor socioeconomic and psychosocial situation. In primate experiments, a submissive stress reaction is followed by a syndrome essentially identical to that seen in humans with visceral obesity, including visceral fat accumulation. These observations strongly support a similar chain of events in humans. Recent studies have indicated several abnormalities in cerebrospinal fluid (CSF) concentrations of catecholamines and neuropeptides. In particular, serotonin metabolites and corticotropin-releasing factor (CRF) concentrations are apparently lower than normal. In women with visceral obesity, these low concentrations are associated with food choices that indicate a preference for carbohydrates. This finding emphasizes the importance of serotonin agonists in the treatment of human obesity. It seems possible that such drugs may have effects on metabolic and other symptoms particularly prevalent in abdominal obesity, and that these effects might be independent of the decrease in energy intake. It would seem highly desirable to explore these possibilities further. Such observations may also provide a link between the abnormalities of low serotonin and CRF concentrations in the central nervous system on one hand and peripheral metabolic and other abnormalities on the other.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 7532780 [PubMed - indexed for MEDLINE]

 
17: J Cardiovasc Risk 2000 Oct;7(5):325-31 Related Articles,

The insulin resistance syndrome: impact on lipoprotein metabolism and atherothrombosis.

Ginsberg HN, Huang LS.

Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. ginsbhe@cudept.cis.columbia.edu

Insulin resistance is a common metabolic abnormality that is associated with an increased risk of both atherosclerosis and type 2 diabetes. The phenotype of insulin resistance includes a dyslipidemia characterized by an elevation of very low-density lipoprotein triglyceride, a reduction in high-density lipoprotein cholesterol, and the presence of small, triglyceride-enriched low-density lipoproteins. The underlying metabolic abnormality driving this dylipidemia is an increased assembly and secretion of very low-density lipoprotein particles, leading to an increased plasma level of triglyceride. Hypertriglyceridemia, in turn, results in a reduction in the high-density lipoprotein level and the generation of small, dense low-density lipoproteins; these events are mediated by cholesteryl ester transfer protein. In addition, hypertension, obesity, and a prothrombotic state are also integral components of the insulin resistance syndrome. In this review, we will provide a pathophysiologic basis, based on studies on humans and in tissue culture, for the dyslipidemia of insulin resistance. We will also review the effects of insulin resistance on the coagulation and fibrinolytic pathways. It is hoped that this review will allow health professionals better to evaluate and treat their patients with insulin resistance, thereby reducing the very much increased risk of atherosclerotic cardiovascular disease carried by these individuals.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11143762 [PubMed - indexed for MEDLINE]

 
18: Ann Endocrinol (Paris) 2001 Sep;62(4 Pt 2):S23-9 Related Articles,

[Obesity and cardiovascular risk]

[Article in French]

Krempf M, Farnier M.

Clinique d'Endocrinologie, Hotel-Dieu, 44093 Nantes. mkrempf@sante.univ-nantes.fr

Overweight and obesity are recognised as responsible for an increase in vascular risk and in excess mortality due to cardio-vascular diseases. This is especially true in presence of increased visceral (central) fat distribution, a key factor for insulin-resistance, the main component of the metabolic syndrome X. Cardio-vascular risk in overweight and obese subjects appears strongly correlated with the common risk factors, more frequently present in these patients: type 2 diabetes, hypertension, lipid abnormalities. Weight reduction improves all risk factors and decreases the patient's global vascular risk. The improvement in the various risk factors is significant with a moderate weight loss (10% of the initial weight). Weight reduction should been obtained always with nutritional-hygienic means (physical activity, weight-reducing diet...) maintained for several months. Only when these approaches appear to be insufficient, the need for an associated pharmacological treatment has to be considered. Amongst the weight-reducing drugs currently available or close to be, orlistat has demonstrated its interest in the glycemic control of type 2 diabetic patients, and its favourable effect in hypertensive patients. Available clinical studies have clearly shown the more marked effect of orlistat in comparison to placebo in reducing the various risk factors. So far, few studies have been conducted to assess the effects of the specific drug therapy on the control of metabolic abnormalities and risk factors in overweight or obese patients, except in type 2 diabetic patients for whom, most of the oral anti-diabetic agents have been tested in overweight or obese diabetic population.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11787368 [PubMed - indexed for MEDLINE]

19. Lopaschuk GD. Improvement of energy metabolism in the ischemic heart. J Mol Cell Cardiol. 2001;33:A154.

20: Circ Res 2000 Mar 17;86(5):580-8 Related Articles,

Comment in:

Click here to read 
The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.

Kantor PF, Lucien A, Kozak R, Lopaschuk GD.

Cardiovascular Research Group and the Division of Pediatric Cardiology, University of Alberta, Edmonton, Canada.

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.

PMID: 10720420 [PubMed - indexed for MEDLINE]

 
21: Cardiovasc Drugs Ther 1998 Dec;12(6):543-9 Related Articles,

Effects of trimetazidine on metabolic and functional recovery of postischemic rat hearts.

Allibardi S, Chierchia SL, Margonato V, Merati G, Neri G, Dell'Antonio G, Samaja M.

Dipartimento di Scienze e Technologie Biomediche, Universita degli Studi di Milano, Italy.

The objective of this study was to test the hypothesis that the beneficial effect of trimetazidine during reflow of ischemic hearts is mediated by energy sparing and ATP pool preservation during ischemia. Isolated rat hearts (controls and rats treated with 10(-6) M trimetazidine, n = 17 per group) underwent the following protocol: baseline perfusion at normal coronary flow (20 minutes), low-flow ischemia at 10% flow (60 minutes), and reflow (20 minutes). We measured contractile function, O2 uptake, lactate release, venous pH and PCO2, and the tissue content of high-energy phosphates and their metabolites. During baseline, trimetazidine induced higher venous pH and lower PCO2 without influencing performance and metabolism. During low-flow ischemia, trimetazidine reduced myocardial performance (P = 0.04) and ATP turnover (P = 0.02). During reflow, trimetazidine improved performance (91 +/- 6% versus. 55 +/- 6% of baseline), prevented the development of diastolic contracture and coronary resistance, and reduced myocardial depletion of adenine nucleotides and purines. ATP turnover during low-flow ischemia was inversely related to recovery of the rate-pressure product (P = 0.002), end-diastolic pressure (P = 0.007), and perfusion pressure (P = 0.05). We conclude that trimetazidine-induced protection of ischemic-reperfused hearts is also mediated by energy sparing during ischemia, which presumably preserves the ATP pool during reflow.

PMID: 10410824 [PubMed - indexed for MEDLINE]
 
22: Am J Cardiol 1998 Oct 1;82(7):898-901 Related Articles,
Click here to read 
Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease.

Lu C, Dabrowski P, Fragasso G, Chierchia SL.

Istituto Scientifico H. San Raffaele, Milan, Italy.

We studied 15 patients with chronic coronary artery disease (13 men aged 62 +/- 8 years) undergoing dobutamine (5 to 40 microg/kg/min) echocardiography at the end of two 15-day treatment periods with placebo and trimetazidine (20 mg 3 times daily) given in random order, according to a double-blind, crossover design. Results show that trimetazidine improves resting left ventricular function and reduces the severity of dobutamine-induced ischemic myocardial dysfunction.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 9781975 [PubMed - indexed for MEDLINE]

 
23: Br J Clin Pharmacol 1994 Mar;37(3):279-88 Related Articles,

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P.

Saint-Luc University Hospital, Brussels, Belgium.

1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 8198938 [PubMed - indexed for MEDLINE]

 
24: Cardiovasc Drugs Ther 1990 Aug;4 Suppl 4:853-9 Related Articles,

Comparison of trimetazidine with nifedipine in effort angina: a double-blind, crossover study.

Dalla-Volta S, Maraglino G, Della-Valentina P, Viena P, Desideri A.

Department of Clinical Medicine, University of Padova Medical School and Hospital, Italy.

Trimetazidine has been shown to have an antianginal effect, increasing exercise capability without producing any significant change of heart rate or systolic blood pressure. The aim of this study was to compare trimetazidine efficiency to that of another classical antianginal drug. A double-blind crossover trimetazidine versus nifedipine trial was carried out in 39 male patients, mean age 58 years, with effort angina for 5 years on average, and a mean number of weekly attacks of 2.4. Thirteen patients had previous myocardial infarction. Nineteen patients received nifedipine (40 mg per day) then trimetazidine (60 mg per day), and 20 patients received the drugs in the opposite order. Each therapeutic period of 6 weeks was preceded by 1 week of washout with placebo. Drug efficacy was assessed by a bicycle exercise tolerance test, performed at the beginning and at the end of each therapeutic period, and by clinical symptoms observed with placebo or with treatment. The statistical analysis was performed according to a crossover design, with repeated measurements. The decrease of the number of weekly attacks was not significantly different with trimetazidine and nifedipine. Results on the exercise test showed no significant differences for maximum workload, the duration of exercise, ST-segment depression at peak exercise, and the time to 1-mm ST-segment depression. Heart rate and systolic blood pressure were not significantly different at rest and at peak exercise. However, the change in the rate-pressure product at the same workload differed significantly between the drugs: It decreased with nifedipine and remained unchanged with trimetazidine, indicating the difference to be in the mode of action of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 2093381 [PubMed - indexed for MEDLINE]

 
25: Eur Heart J 2001 Dec;22(24):2267-74 Related Articles,
Click here to read 
Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand.

Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, Skibinska E, Szymczak K, Swiatek J, Winter M.

Department of Ischemic Heart Disease, National Institute of Cardiology, Warsaw, Poland.

AIMS: To assess the antiischaemic efficacy and tolerability of the metabolic agent trimetazidine in combination with metoprolol in patients with stable effort angina. METHODS: This was a randomized, multicentre, double-blind, placebo-controlled parallel group study. A total of 426 male and female patients with stable, effort-induced angina and documented coronary artery disease received either placebo or trimetazidine 20 mg three times daily in addition to metoprolol 50 mg twice daily. Treadmill exercise tests were performed at weeks (-1), 0, 4 and 12. RESULTS: After 12 weeks, there were significantly greater improvements in the metoprolol + trimetazidine group than in the metoprolol + placebo group in: time to 1 mm ST segment depression, total workload, time to onset of angina, maximum ST segment depression, mean weekly number of angina attacks, mean weekly nitrate consumption, and grade of anginal pain. There was no evidence of any development of tolerance to trimetazidine. The tolerability of trimetazidine was excellent. CONCLUSIONS: Therapy with trimetazidine plus metoprolol produced significant improvements in exercise stress tests and the symptoms of angina relative to metoprolol alone. With its metabolic effect, devoid of any haemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker. Copyright 2001 The European Society of Cardiology.

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 11728147 [PubMed - indexed for MEDLINE]

26. Michaelides AP, Spiropoulos K, Dimopoulos K, et al. Antianginal efficacy of the combination of trimetazidine propranolol compared with isosorbide dinitrate propranolol in patients with stable angina. Clin Drug Invest. 1997;13:8–14.

27: Heart 1997 Oct;78(4):353-7 Related Articles,
Click here to read 
Combination treatment with trimetazidine and diltiazem in stable angina pectoris.

Manchanda SC, Krishnaswami S.

Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India.

OBJECTIVE: To assess antianginal efficacy and possible adverse haemodynamic effects of combination treatment with trimetazidine and diltiazem in patients with stable angina. DESIGN: Double blind, randomised, placebo controlled trial of four weeks duration. SETTING: Outpatient department of two Indian hospitals. SUBJECTS: 64 male patients with stable angina, uncontrolled on diltiazem alone. INTERVENTIONS: Diltiazem 180 mg and trimetazidine 60 mg, or diltiazem 180 mg and placebo daily. MAIN OUTCOME MEASURE: Change in exercise time to 1 mm ST segment depression. RESULTS: 33 patients (55%) had no exercise induced angina at 3 mm ST segment depression at inclusion in the study (silent ischaemia). Intention to treat analysis showed that of 32 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was: for anginal attacks, 28 (87.5) v 15 (46.9), p < 0.001; for exercise time to 1 mm ST segment depression, 21 (65.6) v 9 (28.1), p < 0.003; for exercise time to angina, 12 (37.5) v 5 (15.6), p < 0.05; and for maximum work at peak exercise, 17 (53.1) v 8 (25), p < 0.02. Compared to placebo, there was net improvement with trimetazidine in mean anginal attacks of 4.8/ week (95% confidence interval (CI) 7.5 to 2.1; p < 0.002); in mean exercise times at 1 mm ST segment depression of 94.2 seconds (95% CI 182.8 to 5.6; p < 0.05), and at onset of angina of 113.1 seconds (95% CI 181.6 to 44.6; p < 0.02); and in mean maximum work at peak exercise of 1.4 metabolic equivalents (95% CI 2.4 to 0.3; p < 0.05). CONCLUSIONS: Patients with stable angina uncontrolled with diltiazem had a clinically important improvement after combination treatment with trimetazidine, without adverse haemodynamic events or increased side effects.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 9404250 [PubMed - indexed for MEDLINE]

 
28: Am J Cardiol 1995 Aug 24;76(6):12B-16B Related Articles,

Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators.

Levy S.

Division of Cardiology, Hopital Nord, University of Marseille School of Medicine, France.

The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with beta blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been studied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oral diltiazem (60 mg three times daily). This was a multicenter, placebo-controlled study with a follow-up period of 6 months. Patients with stable angina and a positive exercise electrocardiogram before and after 15 days of diltiazem therapy were included. The 67 patients were randomized to diltiazem plus placebo (group I, 35 patients) and diltiazem plus trimetazidine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physical examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, defined as the time to 1-mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of therapy in both groups showed that the ischemic threshold was significantly prolonged (2 minutes 41 seconds; p < 0.001) in group II. This was not the case for group I, which showed a 41-second prolongation only (difference not significant). The work (kPM) produced at 1-mm ST-segment depression was also significantly increased in group II (1,445.9 kPM; p < 0.001) compared with group I (563.7 kPM; p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 7645522 [PubMed - indexed for MEDLINE]

 
29: Cardiovasc Drugs Ther 1999 May;13(3):217-22 Related Articles,

The antiischemic effects and tolerability of trimetazidine in coronary diabetic patients. A substudy from TRIMPOL-1.

Szwed H, Sadowski Z, Pachocki R, Domzal-Bochenska M, Szymczak K, Szydlowski Z, Paradowski A, Gajos G, Kaluza G, Kulon I, Wator-Brzezinska A, Elikowski W, Kuzniak M.

National Institute of Cardiology, Warsaw, Poland.

Diabetes mellitus, a disease with a wide prevalence, has major cardiovascular effects, being a risk factor for the development of ischemic heart disease and congestive heart failure. The aim of this open, multicenter study was to assess the antiischemic efficacy and tolerability of trimetazidine, a metabolic agent acting at the myocardial mitochondrial level, in diabetic patients with stable effort angina treated previously with a single conventional antianginal drug. Fifty diabetic patients (mean age 58 years) with proven coronary artery disease, stable effort angina for at least 3 months, and positive, comparable results of two initial treadmill exercise tests separated by a 1-week interval were included in the study. They continued their conventional antianginal monotherapy with a long-acting nitrate, beta-blocker, or calcium channel blocker. After stabilization, 4-week therapy with trimetazidine, three times daily, 20 mg was initiated in combination with previous treatment. The results showed a significant improvement in exercise tolerance (440.2 vs. 383.2 s; P < 0.01), time to 1-mm ST-segment depression (358.3 vs. 301.6 s; P < 0.01), time to onset of anginal pain (400.0 vs. 238.3 s; P < 0.01), and total work (9.39 vs. 8.67 metabolic equivalents, P < 0.01). Maximal ST-segment depression was attenuated compared with baseline (1.82 vs. 1.91 mm). Other findings included a significant decrease in the mean frequency of anginal episodes (3.06 vs. 4.79 per week; P < 0.01) and in mean nitrate consumption (2.29 vs. 4.2 doses/week). These results suggest that trimetazidine may be effective and is well tolerated as combination therapy for diabetic coronary artery disease patients uncontrolled with a single hemodynamic agent.

Publication Types:
  • Clinical Trial
  • Multicenter Study


PMID: 10439884 [PubMed - indexed for MEDLINE]

30. Fragasso G, Piatti PM, Monti L, et al. Short- and long-term beneficial effects of trimetazidine in diabetic patients with ischemic dilated cardiomyopathy. J Am Coll Cardiol. 2002. In press.


Although great care has been taken in compiling the information given in this website,
the publisher or the sponsor is not responsible for the continued currency of the information,
for any errors or omissions, or for any consequence arising therefrom.
© 2010 Les Laboratoires Servier