We studied the effect of metformin on hemodynamic and rheological responses to L-arginine in patients with NIDDM. RESEARCH DESIGN AND METHODSâ ...
Metformin Improves Hemodynamic and Rheological Responses to L-Arginine in NIDDM Patients RAFFAELE MARFELLA, MD RITA ACAMPORA, MD GIOVANNI VERRAZZO, MD PATRIZIA ZICCARDI, MD
NICOLETTA D E ROSA, MD RlCCARDO GlUNTA, MD DARIO GIUGLIANO, MD
OBJECTIVE — The endothelium plays a pivotal role in the regulation of vascular tone by releasing nitric oxide (NO). Increased availability of i.-arginine, the natural precursor of NO, induces vasodilatation and inhibits platelet activity. We studied the effect of metformin on hemodynamic and rheological responses to L-arginine in patients with NIDDM. RESEARCH DESIGN A N D METHODS— Ten newly diagnosed NIDDM patients with mild fasting hyperglycemia (7.5 ± 0.3 mmol/1) and without evidence of both micro- and macrovascular complications were investigated. They received an intravenous infusion of Larginine (1 g/min for 30 min) with evaluation of plasma glucose and insulin, systolic (sBP) and diastolic (dBP) blood pressure, heart rate and plasma catecholamines, platelet aggregation, and blood viscosity and filterability. The L-arginine test was repeated after an 8-week treatment with metformin (850 mg b.i.d.). RESULTS — Metformin treatment significantly reduced basal fasting plasma glucose, HbAlc, and platelet aggregation to ADP (P < 0.05); the other parameters did not change. During pretreatment test, i.-arginine infusion decreased sBP (from 137 ± 4.1 to 129 ± 4.5 mmHg, P < 0.01) and dBP (from 79 ± 1.9 to 75 ± 1.2 mmHg, P < 0.01) without affecting heart rate or plasma catecholamines. Both platelet aggregation and blood viscosity showed significant decrements after i.-arginine, while blood filterability did not change. After metformin treatment, the decrease in blood pressure after L-arginine infusion was significantly enhanced, with a maximal decrease of sBP of 12 ± 3.4 mmHg (8 ± 2.5 mmHg pretreatment, P < 0.05) and dBP of 9.5 ± 2.4 mmHg (4.5 ±1.9 mmHg pretreatment, P < 0.01). Heart rate, plasma norepinephrine levels, and blood filterability also rose significantly (P < 0.05-0.01). The decrease in both platelet aggregation and blood viscosity after L-arginine was significantly amplified after metformin. CONCLUSIONS — We conclude that L-arginine infusion in newly diagnosed NIDDM patients without vascular complications produces relevant hemodynamic and rheological changes, which are amplified by an 8-week treatment with metformin. Whether these vascular effects of metformin will improve the poor cardiovascular outlook of the diabetic patient is still unknown.
T
he biguanide metformin is an oral antihyperglycemic agent used in the management of NIDDM. Metformin treatment reduces blood glucose levels by decreasing hepatic glucose output and improving the sensitivity of muscle to insulin without affecting the secretion of this hormone (1-3). A report from the
ongoing United Kingdom Prospective Diabetes Group (UKPDG) (4) shows equivalent antihyperglycemic efficacy for metformin, sulfonylureas, and insulin in the treatment of patients with newly diagnosed NIDDM. Unlike sulfonylureas, metformin does not stimulate insulin secretion, promote weight gain, or cause
[•"rom the Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy. Address correspondence and reprint requests to Dario Giugliano, MD, Via Emilia 1,80021 Afragola (NA), Italy. Received for publication 5 December 1995 and accepted in revised form 18 April 1996. ANOVA, analysis of variance; GV, coefficient of variation; dBP, diastolic blood pressure; NO, nitric oxide; sBP, systolic blood pressure; UKPDG, United Kingdom Prospective Diabetes Group.
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hypoglycemia. Furthermore, it has beneficial effects on metabolic and fibrinolytic variables (3), which may be useful in improving the vascular abnormalities of the diabetic patient (5). The endothelium plays a pivotal role in the regulation of vascular smooth muscle tone by releasing nitric oxide (NO), which is now considered the most potent vasodilating substance (6). Larginine is the natural precursor of NO (6) and may be useful to assess endotheliumdependent vascular function in humans. So far, the systemic infusion of i.-arginine has been shown to reduce blood pressure in healthy subjects (7-9) and patients with hypertension (10) or uncomplicated IDDM (11). The aim of the present study was to assess whether metformin could affect endothelium-dependent vascular responses in patients with diabetes. We investigated the hemodynamic and rheological responses to L-arginine infusion in newly diagnosed NIDDM patients with mild fasting hyperglycemia to avoid the confounding effect of marked variations of the glycemic control. RESEARCH DESIGN A N D M E T H O D S — We studied 10 patients with newly diagnosed NIDDM (5 men, 5 women). Their mean (±SE) age was 47 ± 0.8 years, and their BMI (kg/m2) was 28.1 ±0.7. No significant change in their weight has occurred in the previous months. The patients had no evidence of diabetic retinopathy (on funduscopy), neuropathy (by vibration perception threshold and cardiovascular reflex tests), nephropathy (urinary albumin excretion 90%.
CONCLUSIONS— In this study, metformin led to an improvement of hemodynamic and rheological changes after systemic L-arginine administration in NIDDM patients. In particular, metformin treatment significantly enhanced Posttreatment L-arginine test. The rise in plasma glucose and insulin blood pressure, platelet aggregation, and concentrations in response to L-arginine blood viscosity decrease in response to Lstimulation was not affected by met- arginine, as well as bloodfilterabilityand formin, with values that were not signifi- heart rate increase. All of this occurred cantly different from those recorded dur- even if most basal parameters, like arterial blood pressure, blood filterability and vising pretreatment test (Table 2). The drop in both sBP and dBP cosity, and heart rate, were not signifiduring L-arginine infusion was signifi- cantly affected by metformin. The signifiDIABETES CARE, VOLUME 19, NUMBER 9, SEPTEMBER 1 9 9 6
Marfella and Associates
Table 3—Maximum changes of platelet aggregation, blood viscosity, and filterability, plasma epinephrine and norepinephrine after L-arginine infusion before and after metformin treatment in NIDDM patients Before
metformin Platelet aggregation (%) Blood viscosity (cp) Blood filterability (ml/min) Hpinephrine (ng/1) Norepinephrine (ng/1)
-11 -0.4 0.01 -4 -13
±3.5* ± 0.09* ± .001 ± 3.9 ±8
After metformin -18 ±4.7* -0.8 ± 0.1* 0.12 ± 0.04* 6±4 40 ± 15*
Net
change
P value
- 7 ±3.1 -0.4 ±0.15 0.11 ±0.05
P < 0.05 P < 0.05 P
