Lowering of LDL Cholesterol Rather Than Moderate Weight Loss Improves Endothelium-Dependent Vasodilatation in Obese Women With Previous Gestational Diabetes

Abstract

OBJECTIVE -Effects of weight loss on vascular function are unknown. We compared, in the face of similar weight loss over 3-6 months, effects of orlistat (120 mg t.i.d., n ϭ 23) and placebo (n ϭ 24) on in vivo endothelial function in a high-risk group of obese (BMI 32.1 Ϯ 0.4 kg/m 2 ) premenopausal nondiabetic women with a history of gestational diabetes. RESEARCH DESIGN AND METHODS-Forearm blood flow responses to intraarterial infusions of acetylcholine (ACh) and sodium nitroprusside (SNP), body composition, and serum lipids were determined before and after weight loss.RESULTS -Weight loss averaged 7.3 Ϯ 0.2 kg (8.3 Ϯ 0.1%) and 7.4 Ϯ 0.2 kg (8.2 Ϯ 0.1%) of initial body weight in the orlistat and placebo groups, respectively. Forearm and body compositions changed similarly in both groups. Responses to ACh increased by 41% to the low dose (5.9 Ϯ 0.6 vs. 8.3 Ϯ 0.3 for flow in the experimental/control arm, P Ͻ 0.01) and by 33% to the high dose (7.6 Ϯ 0.8 vs. 10.1 Ϯ 0.6, P Ͻ 0.001) in the orlistat group, but they remained unchanged in the placebo group. The blood flow responses to SNP did not differ significantly between the groups. LDL cholesterol decreased significantly in the orlistat group from 3.5 Ϯ 0.2 to 3.0 Ϯ 0.1 mmol/l (P Ͻ 0.01) but remained unchanged in the placebo group. Within the orlistat group, the decrease in LDL cholesterol correlated significantly with the improvement in the blood flow response to ACh (r ϭ Ϫ0.44, P Ͻ 0.05).CONCLUSIONS -Orlistat but not moderate (8%) weight loss per se improves endothelial function in women with previous gestational diabetes. This improvement is associated with a lowering of LDL cholesterol by orlistat. Diabetes Care 26:1667-1672, 2003E ndothelial dysfunction, defined as an impairment of endothelium-dependent vasorelaxation caused by a loss of nitric oxide (NO) bioactivity in the vessel wall, is considered an early functional change preceding atherosclerosis (1). Obesity is associated with endothelial dysfunction (2-7). In these studies, both obesity (2) and associated metabolic abnormalities such as dyslipidemia (4), hypertension (5), insulin resistance (4), and accumulation of fat in intra-abdominal rather than subcutaneous depots (3,6,7) have correlated with altered vascular function. The exact cause of endothelial dysfunction in obesity is, however, unclear.Weight loss has beneficial effects on multiple markers of cardiovascular risk (8). Their magnitude of improvement is proportional to the amount of weight loss (8). Modest weight loss (5-10%) may not always result in significant long-term changes in risk factors. Effects of weight loss of any magnitude on endotheliumdependent and -independent vasodilatory responses have not been studied.Orlistat is a lipase inhibitor that prevents fat absorption, facilitates weight loss, and prevents weight regain (9). Although most effects of orlistat are attributable to weight loss, it lowers LDL cholesterol more than expected from weight loss alone (10). The latter may be beneficial for vascular function because lowering of ...

Effect of weight loss on inflammatory and endothelial markers and FMD using two low-fat diets

“…In Bergholm's study weight loss of 7 kg was achieved using a moderate fat (30% of energy), highcarbohydrate diet, (50% of energy) with or without orlistat. 11 Improved endothelial function in the orlistat-treated group correlated with reductions in LDL-C Whereas in Brook's study subjects lost similar amounts of weight on an energy restricted diet with 30% energy as fat, LDL-C fell without an effect on FMD. We have observed impairment of FMD in response to a high saturated fat diet compared to high monounsaturated fat, high polyunsaturated fat or low-fat diets in weight stable subjects.…”

“…However, the mechanism of the vascular responses to either endothelium-dependent FMD used in our study or to intravenous arginine used by Ziccardi et al 7 may differ, even if NO acting on vascular smooth muscle is the final pathway. Recently Bergholm et al 11 reported improvements in endothelium-dependent vasodilatation in an orlistat treated group following similar weight loss on either orlistat or placebo. A reduction in LDL-C, seen in the orlistat group only, but not weight loss per se, correlated with the improvements in blood flow.…”

“…[7][8][9][10] However, reductions in LDL cholesterol and fasting glucose concentrations but not weight loss per se were associated with improvements in FMD. [11][12][13] Disturbed endothelial function can also be assessed using the level of molecules secreted by the endothelium such as adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), soluble intracellular adhesion molecule-1 (sI-CAM1), E-selectin, plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (TPa), and there is evidence that these molecules decrease after weight loss. 14 Whether the changes seen in these molecules reflect the changes seen in endothelial nitric oxide (NO)-dependent processes such as FMD or small vessel compliance is not known.…”

Gestational Diabetes, Pregnancy Hypertension, and Late Vascular Disease

“…However, neither BMI nor insulin response to an oral glucose challenge were independently associated with flow-mediated vasodilation. Moreover, moderate (8%) weight reduction does not affect the reduced brachial artery flow-mediated vasodilation in women with a history of GDM (21). These data suggest that, at least macrovascular, endothelial dysfunction may be a response to mildly elevated ambient glucose concentrations but may not reflect insulin resistance.…”

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

“…In the same study population, those with impaired fasting glucose had a 2.8 fold relative risk of cardiovascular events over a 4-year follow up period (Meigs et al 2002). Vascular dysfunction has been identifi ed in several groups of patients with normal blood glucose levels but insulin resistance including; fi rst degree relatives of patients with DM2 (Balletshofer et al 2000), patients with previous history of gestational diabetes (Bergholm et al 2003), patients with metabolic syndrome and patients with polycystic ovarian syndrome (reviewed in Caballero 2005). In the San Antonio heart study, impaired glucose tolerance was associated with hypertension, dyslipidemia, obesity and metabolic syndrome (Haffner et al 1990).…”