- Email: [email protected]
Endothelium-dependent dilatation in patients with type 2 diabetes
READERS’ COMMENTS Endothelium-Dependent Dilatation in Patients With Type 2 Diabetes
We note with interest the study by Gaenzer et al1 showing that in 21 poorly controlled type 2 diabetic patients, endothelial-dependent dilatation (EDD) improved after 3 months of insulin treatment. We have previously performed a randomized controlled trial in patients with poorly controlled type 2 diabetes showing that despite a reduction in hemoglobin A1c, EDD remained unchanged.2 Briefly, 43 patients with type 2 diabetes were randomized to either improved glycemic control or usual glycemic control for a 20-week study period. In the improved control group, hemoglobin A1c decreased from 10.8 ⫾ 0.24% to 8.02 ⫾ 0.25%, but was unchanged in the usual-care group (10.47 ⫾ 0.23% to 10.23 ⫾ 0.23% [group by time intervention effect], p ⬍0.0001). Despite the hemoglobin A1c being 2.2% (95% confidence interval 1.5 to 2.9%; p ⬍0.0001) lower in the improved control group, no change in EDD was detected: improved control group, 5.1 ⫾ 0.6% to 4.9 ⫾ 0.6%; usual control group, 4.2 ⫾ 0.5% to 3.1 ⫾ 0.5% (group by time intervention effect, p ⫽ 0.23). The study by Gaenzer et al was not randomized and there was no control group after intervention. Moreover, important clinical differences existed between the control group and the patients with type 2 diabetes at baseline. The control group weighed less, had lower systolic and diastolic blood pressures, and higher high-density lipoprotein cholesterol and triglyceride concentrations. These important confounding factors are likely to have an impact on EDD. Several other important differences exist between the 2 studies. First, the diabetic patients in our Letters (from the United States) concerning a particular article in The American Journal of Cardiology姞 must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 doublespaced typewritten pages. Two copies must be submitted.
446
study had a significantly higher preintervention EDD—this despite mean preischemia vessel diameter being greater in our study (baseline brachial artery diameter range 4.46 ⫾ 0.16 to 4.66 ⫾ 0.15 mm vs 4.2 ⫾ 0.7 to 4.3 ⫾ 0.6 mm). Moreover, repeat testing for biologic variables is important where regression to the mean may occur. It is conceivable that repeat measurements of EDD would fall closer to a higher mean value in the absence of any intervention. A potentially additional important difference between the studies was the use of insulin prestudy in 7 patients in the improved control group and in 2 patients in the usual control group in our study. Insulin is a vasodilator; the fasting insulin concentration in the improved group was relatively low (week 0, 13.8 ⫾ 5.7 mU/L; week 20, 37.6 ⫾ 6.2 mU/ L), and thus is unlikely to have had a marked effect on vasodilatation.3 We were not able to demonstrate an improvement in EDD despite a significant reduction in hemoglobin A1c. Body mass increased significantly in our improved control group, and in these patients, body mass, in particular fat mass, was the most important predictor of increased soluble adhesion molecule and decreased nitric oxide concentration.4 Thus, weight gain in the improved control group may have offset any benefit accrued by better glycemic control. Although it is encouraging that Gaenzer et al were able to demonstrate an improvement in EDD with improved glycemic control, the randomized controlled trial we performed did not show similar results. In our view, it is likely that a multiple risk factor intervention is required, including correction of dyslipidemia and reduction in blood pressure, to improve EDD and ultimately reduce cardiovascular morbidity and mortality in patients with type 2 diabetes.
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 August 15, 2002
Warwick Bagg, Gillian A. Whalley,
MD
MHSc
Geoffrey D. Braatvedt, MD Auckland, New Zealand 4 April 2002 1. Gaenzer H, Neumayr G, Marschang P, Strum W,
Lechleitner M, Fo¨ger B, Kirchmair R, Patsch J. Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus. Am J Cardiol 2002;89:431–434. 2. Bagg W, Whalley GA, Gamble G, Drury PL, Braatvedt GD. The effects of improved glycaemic control on endothelial function in patients with type 2 diabetes. Int Med J 2001;31:322–328. 3. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 1990;85:1844 –1852. 4. Bagg W, Ferri C, Desideri G, Gamble G, Ockelford P, Braatvedt GD. The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86:5491–5497. PII S0002-9149(02)02425-6
Failure to Recognize Prodromal Symptoms in Patients With Acute Myocardial Infarction and Missing Out On a Way to Reduce Time to Treatment
I am responding to an article by Goldberg et al.1 The investigators studied factors associated with delays in seeking medical care in a large multinational registry of patients with acute myocardial infarction (AMI) and unstable angina pectoris (UAP). The Global Registry of Acute Coronary Events (GRACE) project found that the average and median delay times were longest in the patients with non–ST-elevation AMI and UAP when compared with the patients with ST-elevation AMI. They concluded that the results of the study demonstrated that a large proportion of patients delayed seeking medical care after the onset of acute coronary symptoms and remained in need of “targeted educational efforts” to reduce the extent of delays. About 50% of patients with AMI present with intermittent chest symptoms usually not perceived as chest pain. Such symptoms have been called preinfarction angina, prodromal unstable angina, waxing and waning angina, winking and blinking angina, premonitory angina, and so on. Approximately 50% of patients with AMI are “her-
We note with interest the study by Gaenzer et al1 showing that in 21 poorly controlled type 2 diabetic patients, endothelial-dependent dilatation (EDD) improved after 3 months of insulin treatment. We have previously performed a randomized controlled trial in patients with poorly controlled type 2 diabetes showing that despite a reduction in hemoglobin A1c, EDD remained unchanged.2 Briefly, 43 patients with type 2 diabetes were randomized to either improved glycemic control or usual glycemic control for a 20-week study period. In the improved control group, hemoglobin A1c decreased from 10.8 ⫾ 0.24% to 8.02 ⫾ 0.25%, but was unchanged in the usual-care group (10.47 ⫾ 0.23% to 10.23 ⫾ 0.23% [group by time intervention effect], p ⬍0.0001). Despite the hemoglobin A1c being 2.2% (95% confidence interval 1.5 to 2.9%; p ⬍0.0001) lower in the improved control group, no change in EDD was detected: improved control group, 5.1 ⫾ 0.6% to 4.9 ⫾ 0.6%; usual control group, 4.2 ⫾ 0.5% to 3.1 ⫾ 0.5% (group by time intervention effect, p ⫽ 0.23). The study by Gaenzer et al was not randomized and there was no control group after intervention. Moreover, important clinical differences existed between the control group and the patients with type 2 diabetes at baseline. The control group weighed less, had lower systolic and diastolic blood pressures, and higher high-density lipoprotein cholesterol and triglyceride concentrations. These important confounding factors are likely to have an impact on EDD. Several other important differences exist between the 2 studies. First, the diabetic patients in our Letters (from the United States) concerning a particular article in The American Journal of Cardiology姞 must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 doublespaced typewritten pages. Two copies must be submitted.
446
study had a significantly higher preintervention EDD—this despite mean preischemia vessel diameter being greater in our study (baseline brachial artery diameter range 4.46 ⫾ 0.16 to 4.66 ⫾ 0.15 mm vs 4.2 ⫾ 0.7 to 4.3 ⫾ 0.6 mm). Moreover, repeat testing for biologic variables is important where regression to the mean may occur. It is conceivable that repeat measurements of EDD would fall closer to a higher mean value in the absence of any intervention. A potentially additional important difference between the studies was the use of insulin prestudy in 7 patients in the improved control group and in 2 patients in the usual control group in our study. Insulin is a vasodilator; the fasting insulin concentration in the improved group was relatively low (week 0, 13.8 ⫾ 5.7 mU/L; week 20, 37.6 ⫾ 6.2 mU/ L), and thus is unlikely to have had a marked effect on vasodilatation.3 We were not able to demonstrate an improvement in EDD despite a significant reduction in hemoglobin A1c. Body mass increased significantly in our improved control group, and in these patients, body mass, in particular fat mass, was the most important predictor of increased soluble adhesion molecule and decreased nitric oxide concentration.4 Thus, weight gain in the improved control group may have offset any benefit accrued by better glycemic control. Although it is encouraging that Gaenzer et al were able to demonstrate an improvement in EDD with improved glycemic control, the randomized controlled trial we performed did not show similar results. In our view, it is likely that a multiple risk factor intervention is required, including correction of dyslipidemia and reduction in blood pressure, to improve EDD and ultimately reduce cardiovascular morbidity and mortality in patients with type 2 diabetes.
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 August 15, 2002
Warwick Bagg, Gillian A. Whalley,
MD
MHSc
Geoffrey D. Braatvedt, MD Auckland, New Zealand 4 April 2002 1. Gaenzer H, Neumayr G, Marschang P, Strum W,
Lechleitner M, Fo¨ger B, Kirchmair R, Patsch J. Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus. Am J Cardiol 2002;89:431–434. 2. Bagg W, Whalley GA, Gamble G, Drury PL, Braatvedt GD. The effects of improved glycaemic control on endothelial function in patients with type 2 diabetes. Int Med J 2001;31:322–328. 3. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 1990;85:1844 –1852. 4. Bagg W, Ferri C, Desideri G, Gamble G, Ockelford P, Braatvedt GD. The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86:5491–5497. PII S0002-9149(02)02425-6
Failure to Recognize Prodromal Symptoms in Patients With Acute Myocardial Infarction and Missing Out On a Way to Reduce Time to Treatment
I am responding to an article by Goldberg et al.1 The investigators studied factors associated with delays in seeking medical care in a large multinational registry of patients with acute myocardial infarction (AMI) and unstable angina pectoris (UAP). The Global Registry of Acute Coronary Events (GRACE) project found that the average and median delay times were longest in the patients with non–ST-elevation AMI and UAP when compared with the patients with ST-elevation AMI. They concluded that the results of the study demonstrated that a large proportion of patients delayed seeking medical care after the onset of acute coronary symptoms and remained in need of “targeted educational efforts” to reduce the extent of delays. About 50% of patients with AMI present with intermittent chest symptoms usually not perceived as chest pain. Such symptoms have been called preinfarction angina, prodromal unstable angina, waxing and waning angina, winking and blinking angina, premonitory angina, and so on. Approximately 50% of patients with AMI are “her-