Metabolic treatment of diabetic 
coronary patients

H. Szwed
Department of Ischemic Heart Disease, National Institute of Cardiology, Warsaw, Poland
Correspondence: Professor H. Szwed, Department of Ischemic Heart Disease, 
National Institute of Cardiology, Spartanska 1, 02637 Warsaw, Poland (biblnauk@ikard.waw.pl)

Introduction
Diabetic patients suffer from a high incidence of morbidity and mortality from cardiovascular disorders. The incidence of mortality due to cardiac disease is twofold higher in diabetic men and fourfold higher in diabetic women than in their nondiabetic counterparts.[1] Diabetic patients have a two to three times higher risk of atherosclerosis compared with nondiabetic subjects.[2] Diabetes is an independent risk factor for coronary artery stenosis. Atherosclerosis of the epicardial arteries is more severe in diabetic patients than in the general population.[3] Moreover, in patients with diabetes, coronary artery disease leads to more severe left ventricular dysfunction.[4] In the heart of a diabetic patient several metabolic disturbances may be found. The transport of glucose is impaired[5] and the rate of glycolysis is significantly decreased,[6] resulting in a greater reliance on free fatty acids (FFA) as a source of ATP. The high plasma FFA level and increase of FFA oxidation result in metabolic disorders and impaired left ventricular function during and after ischemia in both the normal and the diabetic heart.[7,8] Consequently, there is a rationale for improving patients’ clinical status and contractile function by suppressing FFA oxidation.
Trimetazidine is a metabolic agent with antiischemic properties that operates independently of any hemodynamic changes.[9,10] In a recent study it was demonstrated that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 
3-ketoacyl CoA thiolase activity, resulting in inhibition of FFA oxidation and an increase in glucose oxidation, which protects the ischemic heart.[11] 

TRIMPOL-1
The efficacy of trimetazidine in diabetic patients was demonstrated in the TRIMPOL (Trimetazidine in Poland) studies.[12] The TRIMPOL-1 study was carried out at 100 centers in Poland between 1995 and 1997. It comprised an open multicenter trial divided into two phases: a 1-week observation period (visit W-1–W0) to confirm the stability of the patients’ angina on existing antianginal monotherapy (with a long-acting nitrate, ß-blocker, or calcium antagonist), followed by a 4-week treatment period (W0–W4), during which patients received trimetazidine 20 mg tid in addition to their existing antianginal therapy.

Subjects
Subjects were age 18–70 years, with a history of stable, effort-induced angina for at least 3 months, and documented coronary artery disease (either 70% narrowing in at least one coronary artery on coronary angiography, or previous myocardial infarction). They had to have positive treadmill exercise tests during visits W-1 and W0, and the clinical stability of coronary artery disease confirmed by the difference in time duration (until the appearance of a positive result) of these tests <20%.
Treatment with concomitant antianginal medication (monotherapy with a nitrate, ß-blocker, or calcium antagonist) was continued during both the observation and treatment phases of the study. Other therapies routinely used for coronary artery disease like antiplatelets (aspirin, ticlopidine etc), hypolipemic agents as well as therapies for concomitant diseases, were continued during the study. Short-acting nitrates were recommended to relieve anginal pain.
The study population comprised 700 patients. Among them were 50 diabetic patients who were also included in the subanalysis. Six of these patients had insulin-dependent diabetes and 44 had noninsulin-dependent diabetes. Diabetic patients were treated with insulin (n = 6), oral hypoglycemic agents (n = 28), or diet (n = 16). The patient characteristics at baseline are shown in Table I.

Table I. Characteristics of diabetic patients (n = 50) with coronary heart disease: a TRIMPOL-1 substudy.

Methods
Clinical examinations and maximal treadmill exercise tests (Bruce protocol) were performed at the initial assessment (W-1), at study baseline (W0), and after a 4-week treatment with trimetazidine (W4). A positive exercise treadmill test was defined by either a horizontal or downward sloping depression in ST-segment of 1 mm for >80 ms after J-point and anginal pain, or 1.5 mm ST-segment depression without anginal pain. Laboratory safety assessments were made at W0 and W4. All adverse events, evaluated by investigator questioning and patient information, were recorded. Patients completed a daily diary to report the occurrence of anginal pain and their consumption of interventional short-acting nitrates.
The primary efficacy criteria were: total exercise duration; total work (in MET); time to 1 mm ST-segment depression; and time to onset of anginal pain, evaluated at the exercise treadmill test performed after 4 weeks of therapy with trimetazidine (W4) vs. the study baseline (W0). Secondary assessment criteria were: mean weekly number of angina attacks; mean weekly nitrate consumption; mean Canadian Cardiovascular Society Classification (CCSC) score; and rate-pressure product (heart rate x systolic blood pressure) at peak exercise.

Results
After a 4-week treatment with trimetazidine 20 mg tid, coronary diabetic patients showed significant improvements in all exercise stress test parameters (Table II). 

Table II. Effects of trimetazidine on efficacy parameters in patients with stable angina and diabetes: a TRIMPOL-1 substudy.

Diabetic patients had an improvement in CCSC score compared with baseline.
Evaluation of the patients’ daily diaries showed a significant decrease in the mean number of anginal attacks per week and in weekly nitrate consumption during treatment with trimetazidine. No significant changes in mean rate-pressure product at maximal exercise were noted (Table II).
Data were available on 49 patients for the tolerability and safety analysis. Trimetazidine therapy was well tolerated in the diabetic patients, with only 4 of 49 patients (8%) experiencing adverse events. However, no patients withdrew because of adverse events.
Trimetazidine did not produce any clinically significant changes in laboratory parameters, including glycemia. These results were con-
firmed by both the investigators’ and the patients’ global evaluation of efficacy (Table III).

Table III. Investigators’ and patients’ global evaluation of efficacy after 4 weeks of treatment with trimetazidine in diabetic patients with coronary heart disease: a TRIMPOL-1 substudy.



Conclusion
The results of the TRIMPOL-1 study suggest that in diabetic patients with angina pectoris not controlled by conventional antianginal drugs, the addition of the metabolic agent trimetazidine significantly improves exercise stress test parameters and reduces the clinical symptoms of angina pectoris, with excellent tolerability.

TRIMPOL-2
The results of the efficacy and safety of trimetazidine in stable angina pectoris were confirmed in the TRIMPOL-2 study. This was a multicenter, double-blind, placebo-controlled study, completed in 1999. The final results of the study were presented at the XII Congress of the European Society of Cardiology in Amsterdam in 2000.[13] 

Methods
The study consisted of two phases: a 1-week open study to confirm the stability of disease on existing monotherapy with metoprolol 50 mg bid, followed by a 12-week, double-blind period during which patients randomly received either metoprolol 50 mg bid + trimetazidine 20 mg tid, or metoprolol 50 mg bid + placebo. The primary and secondary assessment criteria were the same as in the TRIMPOL-1 study (parameters were evaluated before and after 4 and 12 weeks of therapy).

Patients and results
The data of 347 patients were available for analysis: 179 in the metoprolol-trimetazidine group and 168 in the metoprolol-placebo group.
After 12 weeks of therapy, trimetazidine produced a significant improvement of all exercise and clinical parameters in comparison with placebo.
Of 347 patients in the per protocol population, 25 were diabetic: 14 in the metoprolol-trimetazidine group and 11 in the metoprolol-placebo group. In a subgroup of diabetic patients, improvements in exercise test parameters were observed after 12 weeks of therapy with trimetazidine, but the differences in improvement were not significant in comparison with placebo because of the small sample size. As in the TRIMPOL-1 study, the tolerability of trimetazidine was excellent.

Summary
The results of the TRIMPOL studies suggest that trimetazidine is both effective and well tolerated in coronary diabetic patients when combined with conventional antianginal agents such as nitrates, ß-blockers, or calcium channel blockers. The TRIMPOL-1 results are novel in that no previous study has investigated the efficacy of trimetazidine in treating angina in diabetic patients. However, these results must be confirmed by a larger, double-blind, randomized study.
Such a study is planned to be carried out in Poland, and will be known as the TRIM-DIAB study (the effects of trimetazidine 35 mg bid in combination with metoprolol 50 mg bid treatment in patients with stable effort angina and type 2 diabetes). It will be a 12-week, double blind, placebo-controlled, multicenter, randomized trial, comprising 400 patients. The design of the study and the evaluation criteria will be similar to those of TRIMPOL-2. 

REFERENCES

 
1: Diabetes Care 1993 Feb;16(2):434-44 Related Articles, Books, LinkOut


Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

Stamler J, Vaccaro O, Neaton JD, Wentworth D.

Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois 60611-4402.

OBJECTIVE--To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. RESEARCH DESIGN AND METHODS--Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11-13 yr). Participants were 347,978 men aged 35-57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality. RESULTS--Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < 0.0001). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels. CONCLUSIONS--These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.

Publication Types:

  • Multicenter Study


PMID: 8432214 [PubMed - indexed for MEDLINE]

 
2: JAMA 1979 May 11;241(19):2035-8 Related Articles, Books, LinkOut

Diabetes and cardiovascular disease. The Framingham study.

Kannel WB, McGee DL.

Based on 20 years of surveillance of the Framingham cohort relating subsequent cardiovascular events to prior evidence of diabetes, a twofold to threefold increased risk of clinical atherosclerotic disease was reported. The relative impact was greatest for intermittent claudication (IC) and congestive heart failure (CHF) and least for coronary heart disease (CHD), which was, nevertheless, on an absolute scale the chief sequela. The relative impact was substantially greater for women than for men. For each of the cardiovascular diseases (CVD), morbidity and mortality were higher for diabetic women than for nondiabetic men. After adjustment for other associated risk factors, the relative impact of diabetes on CHD, IC, or stroke incidence was the same for women as for men; for CVD death and CHF, it was greater for women. Cardiovascular mortality was actually about as great for diabetic women as for diabetic men.

PMID: 430798 [PubMed - indexed for MEDLINE]
 
3: Am Heart J 1997 Dec;134(6):1037-43 Related Articles, Books, LinkOut
Click here to read
Increased incidence of moderate stenosis among patients with diabetes: substrate for myocardial infarction?

Henry P, Makowski S, Richard P, Beverelli F, Casanova S, Louali A, Boughalem K, Battaglia S, Guize L, Guermonprez JL.

Department of Cardiology, Hopital Broussais, Paris, France.

Persons with diabetes are at higher risk for myocardial infarction and sudden death than are persons without diabetes. It has been demonstrated that the artery that occludes during acute myocardial infarction generally had less than 75% stenosis on a previous angiogram. The extent of coronary artery stenosis was analyzed for 820 consecutively examined patients who underwent coronary angiography at our institution. The patients were categorized according to the presence or absence of diabetes mellitus. The severity of stenosis was taken into consideration. Patients with diabetes had moderate (50% to 75% narrowing) stenosis much more frequently than patients without diabetes (50.6 versus 30.3%, p < 0.001). Moreover diabetes mellitus was an independent risk factor for moderate stenosis. The lesions were more frequently located on distal arteries, more frequently had a pattern of three-vessel disease, and had a trend toward more diffuse disease than described 25 years ago. This greater amount of moderate stenosis may be considered a substrate for future acute plaque rupture. It may explain the high prevalence of acute myocardial infarction and sudden death among patients with diabetes without an increase in the incidence of angina pectoris.

PMID: 9424063 [PubMed - indexed for MEDLINE]
 
4: J Am Coll Cardiol 1989 Jul;14(1):49-57 Related Articles, Books, LinkOut

The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group.

Stone PH, Muller JE, Hartwell T, York BJ, Rutherford JD, Parker CB, Turi ZG, Strauss HW, Willerson JT, Robertson T, et al.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.

Patients with diabetes mellitus experience a more adverse outcome after acute myocardial infarction compared with nondiabetic patients, although the mechanisms responsible for these findings are not clear. From the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, the course of acute infarction in 85 diabetic patients was compared with that in 415 nondiabetic patients, all of whom had serial assessments of left ventricular function. The diabetic patients experienced a more complicated in-hospital and postdischarge course than did the nondiabetic patients, including a higher incidence of postinfarction angina, infarct extension, heart failure and death, despite the development of a smaller infarct size and similar levels of left ventricular ejection fraction. Although diabetic patients had a worse profile of cardiovascular risk factors at the time of the index infarction, the increased incidence of adverse outcomes among them persisted despite adjustment for these baseline imbalances. Diabetic women had a poor baseline risk profile compared with the other groups categorized by gender and diabetic status, and experienced an almost twofold increase in cardiac mortality despite development of the smallest infarct size during the index event. The duration of diabetes and the use of insulin at the time of the index infarction were associated with a better in-hospital mortality rate, but the duration of diabetes did not exert a major influence on the outcome of the diabetic patients. The factors responsible for the increased incidence of adverse outcomes among diabetic patients may be related to an acceleration of the atherosclerotic process, diastolic left ventricular dysfunction associated with diabetic cardiomyopathy or other unidentified unfavorable processes.

PMID: 2661630 [PubMed - indexed for MEDLINE]
 
5: J Clin Invest 1984 Sep;74(3):1073-9 Related Articles, Books, LinkOut

Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog.

Barrett EJ, Schwartz RG, Francis CK, Zaret BL.

In vivo small doses of insulin inhibit lipolysis, lower plasma FFA, and stimulate glucose disposal. Lowering of plasma FFA, either in the absence of a change in insulin or during combined hyperglycemia and hyperinsulinemia, promotes glucose uptake by heart muscle in vivo. In the isolated perfused heart, large doses of insulin directly stimulate heart glucose uptake. To assess the effect of physiological elevations of plasma insulin upon myocardial glucose and FFA uptake in vivo independent of changes in plasma substrate concentration, we measured arterial and coronary sinus concentrations of glucose, lactate, and FFA, and coronary blood flow in conscious dogs during a 30 min basal and a 2 h experimental period employing three protocols: (a) euglycemic hyperinsulinemia (insulin clamp, n = 5), (b) euglycemic hyperinsulinemia with FFA replacement (n = 5), (c) hyperglycemic euinsulinemia (hyperglycemic clamp with somatostatin, n = 5). In group 1, hyperinsulinemia (insulin = 73 +/- 13 microU/ml) stimulated heart glucose uptake (7.3 +/- 4.4 vs. 28.2 +/- 2.8 mumol/min, P less than 0.002), lowered plasma FFA levels by 80% (P less than 0.05), and decreased heart FFA uptake (28.4 +/- 4 vs. 1.5 +/- 0.9, P less than 0.01). When the fall in plasma FFA was prevented by FFA infusion (group 2), hyperinsulinemia (86 +/- 10 microU/ml) provoked a lesser (P less than 0.05) stimulation of glucose uptake (delta = 8.2 +/- 4.2 mumol/min) than in group 1, and there was no significant change in FFA uptake (25.3 +/- 16 vs. 16.5 +/- 4). Hyperglycemia (plasma glucose = 186 +/- 8 mg/100 ml) during somatostatin infusion resulted in only a small rise in plasma insulin (delta = 12 +/- 7 microU/ml), and although plasma FFA tended to decline, heart glucose uptake did not rise significantly (delta = 5.5 +/- 3.2 mumol/min, P = NS). There was no significant change in coronary blood flow during any of the three study protocols. We conclude that, in the dog, insulin at physiologic concentrations: (a) stimulates heart glucose uptake, both directly and by suppressing the plasma FFA concentration, and (b) does not alter coronary blood flow. Hyperglycemia per se has little effect on heart glucose uptake.

PMID: 6381537 [PubMed - indexed for MEDLINE]
 
6: Biochim Biophys Acta 1994 Jan 11;1225(2):191-9 Related Articles, Books, LinkOut

Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats.

Gamble J, Lopaschuk GD.

Department of Pharmacology, University of Alberta, Edmonton, Canada.

Stimulation of glucose oxidation by dichloroacetate (DCA) treatment is beneficial during recovery of ischemic hearts from non-diabetic rats. We therefore determined whether DCA treatment of diabetic rat hearts (in which glucose use is extremely low), increases recovery of function of hearts reperfused following ischemia. Isolated working hearts from 6 week streptozotocin-diabetic rats were perfused with 11 mM [2-3H/U-14C]glucose, 1.2 mM palmitate, 20 microU/ml insulin, and subjected to 30 min of no flow ischemia followed by 60 min reperfusion. Heart function (expressed as the product of heart rate and peak systolic pressure), prior to ischemia, was depressed in diabetic hearts compared to controls (HR x PSP x 10(-3) was 18.2 +/- 1 and 24.3 +/- 1 beats/mm Hg/min in diabetic and control hearts respectively) but recovered to pre-ischemic levels following ischemia, whereas recovery of control hearts was significantly decreased (17.8 +/- 1 and 11.9 +/- 3 beats/mm Hg/min in diabetic and control hearts respectively). This enhanced recovery of diabetic rat hearts occurred even though glucose oxidation during reperfusion was significantly reduced as compared to controls (39 +/- 6 and 208 +/- 42 nmol/min/g dry wt, in diabetic and control hearts respectively). Glycolytic rates (3H2O production) during reperfusion were similar in diabetic and control hearts (1623 +/- 359 and 2071 +/- 288 nmol/min/g dry wt, respectively). If DCA (1 mM) was added at reperfusion, hearts from control animals exhibited a significant improvement in function (HR x PSP x 10(-3) recovered to 20 +/- 4 beats/mm Hg/min) that was accompanied by a 4-fold increase in glucose oxidation (from 208 +/- 42 to 753 +/- 111 nmol/min/g dry wt). DCA was without effect on functional recovery of diabetic rat hearts during reperfusion but did significantly increase glucose oxidation from 39 +/- 6 to 179 +/- 44 nmol/min/g dry wt). These data suggest that, unlike control hearts, low glucose oxidation rates are not an important factor in reperfusion recovery of previously ischemic diabetic rat hearts.

PMID: 8280788 [PubMed - indexed for MEDLINE]
 
7: Coron Artery Dis 1996 Feb;7(2):116-23 Related Articles, Books, LinkOut

Abnormal mechanical function in diabetes: relationship to altered myocardial carbohydrate/lipid metabolism.

Lopaschuk GD.

Department of Pediatrics, University of Alberta, Edmonton, Canada.

Publication Types:
  • Review
  • Review, Academic


PMID: 8813442 [PubMed - indexed for MEDLINE]

 
8: Lancet 1968 Apr 6;1(7545):710-4 Related Articles, Books, LinkOut

Relation between serum-free-fatty acids and arrhythmias and death after acute myocardial infarction.

Oliver MF, Kurien VA, Greenwood TW.

PMID: 4170959 [PubMed - indexed for MEDLINE]
 
9: Trends Pharmacol Sci 1989 Oct;10(10):397-400 Related Articles, Books, LinkOut

New anti-ischaemic drugs: cytoprotective action with no primary haemodynamic effects.

Boddeke E, Hugtenburg J, Jap W, Heynis J, van Zwieten P.

Currently therapy for ischaemic heart disease is based on drugs such as beta-adrenoceptor antagonists, Ca2+ antagonists and nitrates, which have pronounced haemodynamic effects. However, these drugs can have adverse reactions including systemic haemodynamic effects, leading to low blood pressure and peripheral oedema in some patients. Recent observations that certain types of Ca2+ antagonist prevent the Ca2+ overload that occurs after ischaemia have led to the design of new anti-ischaemic drugs that are cytoprotective, but have no (or few) haemodynamic effects. In this article, Pieter van Zwieten and colleagues assess the therapeutic potential of these drugs.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 2694536 [PubMed - indexed for MEDLINE]

 
10: Clin Trials Metaanal 1994 Apr;29(1):49-56 Related Articles, Books, LinkOut

Lack of effects of trimetazidine on systemic hemodynamics in patients with coronary artery disease: a placebo-controlled study.

Pornin M, Harpey C, Allal J, Sellier P, Ourbak P.

Service de Cardiologie, Hopital Broussais, Paris, France.

Trimetazidine has been shown to improve anginal symptoms and exercise tolerance in patients with coronary artery disease (CAD). To determine the hemodynamic effects of trimetazidine, systemic hemodynamics were studied in 15 patients suffering from CAD (12 male, 3 female, mean age +/- SEM = 58.6 +/- 1.8 years). Cardiac index was determined by thermodilution method. Left ventricular and aortic pressures were measured using micromanometers (Miller Instruments). After basal measurements, patients were randomly given either placebo (n = 5) or one of two therapeutic doses of trimetazidine 1 mg.kg-1 (n = 5) or trimetazidine 1.5 mg.kg-1 (n = 5) in a double-blind procedure. Data were recorded 5, 10 and 20 min after intravenous drug bolus. Throughout the procedure, the evolution of systemic hemodynamic parameters was not statistically different between the three groups, in particular heart rate, cardiac index, systolic, diastolic and mean aortic pressures, end-diastolic ventricular pressure, mean capillary wedge pressure, pulmonary artery pressures or systemic vascular resistances. We conclude that, unlike other antianginal drugs (particularly beta-blockers, nitrates and calcium-channel inhibitors), trimetazidine does not modify systemic hemodynamics in patients with CAD. These results are consistent with a direct effect of trimetazidine on the ischemic myocardial cell previously reported.

Publication Types:
  • Clinical Trial
  • Randomized Controlled Trial


PMID: 10150185 [PubMed - indexed for MEDLINE]

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

Comment in:

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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]

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

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]


13. Szwed H, Sadowski Z, Elikowski W, et al. Efficacy and safety of trimetazidine in combination with metoprolol in patients with stable effort angina pectoris. TRIMPOL II — double-blind, randomised, placebo-controlled, multicentre trial. Eur Heart J. 2000;21(suppl 363):1921


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