2nd International Conference on Hypertension, Lipids, Diabetes and Stroke Prevention
March 6 - 8, 2008
Prague, Czech Republic
“Freezing!” was probably the first word spoken by attendees to the Hypertension, Lipids, Diabetes and Stroke Prevention meeting upon landing at the airport in Prague; however, once at the meeting venue, science took over, with three days of exciting discussions on the management of stroke risk factors (hypertension, lipids, diabetes, body weight, atherosclerosis). The following report will review a number of oral and poster contributions to the meeting, with the aim of summarizing major therapeutic news disclosed to those who could enjoy a stay in the captivating city of Prague. A major conclusion of data discussed during the meeting is that secondary stroke prevention remains suboptimal, not only in elderly but also in younger patients, with the possible exception of the current high rate of statin use [Gonzalez-Hernandez, A. et al., Abst 1126], although data to demonstrate increasing benefits through increasing compliance with antihypertensive and antidiabetic medication was, once again, presented [Susomboon, T. & Sookaneknun, P., Abst 1230]. Furthermore, with hypertension as one of the major and most common risk factors, data also accumulate indicating that optimizing blood pressure control would reduce the risk of cerebrovascular events, especially in the elderly population [Zorila, C.E. et al., Abst 1240]. By and large, all evidence support the benefits of lowering blood pressure and lipid levels in preventing coronary artery and cerebrovascular disease [Sever, P.S., Abst 1263].
Hypertension is one of the major risk factors for stroke, and adherence to antihypertensive therapy was related to greater reduction of stroke risk in primary prevention, as noted in a cohort of 96,715 essential hypertension patients [Perreault, S. et al., Abst 1117]. Furthermore, at least in experimental animals, antihypertensive therapy could have a favorable impact on amyloid-beta oligomerization, thus preventing Alzheimer’s and related cognitive impairment [Pasinetti, G.M., Abst 1153].
Many therapies are currently available for the treatment of hypertension, although data continue to accrue regarding the superior efficacy of low-dose combinations compared to higher-dose monotherapy or step therapy [Pleyko, O.A. & Konrady, A.O., Abst 1056] (Fig. 1).
Fig. 1. Target blood pressure achievement rates in patients receiving standard monotherapy (indapamide, bisoprolol, amlodipine, fosinopril or rilmenidine), step therapy with addition of a second drug if required, or initial low-dose combination therapy [Pleyko, O.A. & Konrady, A.O., Abst 1056].
Regarding individual drug information, among the calcium channel blockers, nilvadipine but not nitrendipine was suggested to positively modulate lipoprotein metabolism, according to the results of a double-blind trial in 79 hypertensive, hypercholesterolemic individuals [Richter, W.O. & Rafflenbeul, W., Abst 1178] (Fig. 2).
Fig. 2. Percent change in cholesterol levels after 52 weeks of treatment with nilvadipine or nitrenidipine [Richter, W.O. & Rafflenbeul, W., Abst 1178].
The controversy over the alleged superiority of angiotensin receptor blockers over angiotensin-converting enzyme inhibitors will not be clarified until the results of the ONTARGET and other ongoing trials are available [Mourad, J.J., Abst 1262]. The results of the ACCOST trial were discussed in the beautiful city of Prague during the Hypertension, Lipids, Diabetes and Stroke Prevention meeting in March 2008. This two-phase study of candesartan versus placebo (phase I) and candesartan versus angiotensin-converting enzyme inhibitor-based therapy (phase II) in 38 normotensive patients with stroke, from which the phase I, randomized, placebo-controlled results were reported, demonstrated a blood pressure-lowering effect of candesartan without potentially harmful falls [O’Brien, R.E. et al., Abst 1031] (Fig. 3). An alternative angiotensin receptor blocker, telmisartan, was compared to ramipril in terms of effect on endothelial function and inflammatory markers in 39 patients with diabetes and hypertension. Both treatments effectively improved endothelial function and reduced CD40 ligand levels, while lowering blood pressure and urinary albumin excretion rates [Alagona, C. et al., Abst 1105] (Fig. 4).
Fig. 3. Change in systolic and diastolic blood pressure after 4 weeks of treatment with candesartan and placebo in normotensive stroke patients in the ACCOST trial [O’Brien, R.E. et al., Abst 1031].
Fig. 4. Change in urinary albumin excretion in diabetic hypertensive subjects after 3 months of treatment with telmisartan or ramipril [Alagona, C. et al., Abst 1105].
An innovative putative approach to blood pressure control could be the use of milk-derived bioactive Ile-Pro-Pro and Val-Pro-Pro tripeptides, which were shown to modulate enzymes forming angiotensin II (angiotensin-converting enzyme and chymase) with beneficial cardiovascular effects [Jauhiainen, T. et al., Abst 1063]. Other natural therapies for high blood pressure that were discussed in Prague included Spirulina maxima, which demonstrated antihypertensive and hepatoprotective effects in humans [Torres-Duran, P.V. et al., Abst 1187], and cocoa polyphenols, which demonstrated antihypertensive activity in spontaneously hypertensive animals [Quiñones, M. et al., Abst 1193].
Drugs with vasorelaxant effect, but with which direct effects on blood pressure were not demonstrated, included diazepam, which induced vasodilatation of aortic rings [Ziberna, L. et al., Abst 1224]. Through upregulation of ρA/ρ kinase and downregulation of soluble guanyl cyclase pathways, CGS-26303 prevented subarachnoidal hemorrhage-induced vasospasm [Lee, P.Y. et al., Abst 1226]. In a similar way, the Chinese herbal preparation KMUVS-1 (which contains Salvia miltiorrhiza, Carthamus tinctorius, Anredera cordifolia, Ligusticum sinense, Carica papaya, Pheretima sp., Glycyrrhiza sp., Taxillus chinensis, Prunus persica, Achyranthes bidentata, Spatholobus sp., Caesalpinia sappan and Paeonia lactiflora) prevented cerebral vasospasm by blocking endothelin-1 pathways, resulting in neuroprotective activity in experimental animals [Huang, C.J. et al., Abst 1227].
Regarding nonpharmacological approaches, clinical trial data supported the use of auriculopuncture in the management of high blood pressure, with a decrease of 7% of systolic blood pressure demonstrated in six patients [Ahmedov, S., Abst. 1015].
Statins are among the best known and most widely used antihypercholesterolemic drugs, with an additional favorable effect on atherosclerotic plaque vulnerability and stabilization [Harms, L. et al., Abst 1103]. With >80% compliance, an effect was demonstrated in the primary prevention of stroke [Perreault, S. et al., Abst 1116], although prior statin use had no impact on lacunar stroke severity and outcome [Gonzalez-Hernandez, A. et al., Abst 1104]. Furthermore, intensive-dose statin therapy arose as a cost-effective secondary prevention option in patients with acute coronary syndrome, particularly in older subjects [Ward, S.E. & Ara, R.M., Abst 1202].
Regarding specific drugs, while atorvastatin reduced lipoperoxidation in metabolic syndrome patients [Zorila, C.E. et al., Abst 1241] and demonstrated an effect in improving hemorrheological parameters, endothelial function, platelet aggregation and homeostasis in 27 patients with chronic cerebrovascular disease [Szapary, L. et al., Abst 1229], simvastatin use in patients with subarachnoid hemorrhage is being assessed in the currently ongoing STASH double-blind, placebo-controlled trial [Kirkpatrick, P.J. et al., Abst 1197]. Comparing a statin, fluvastatin, and a fibrate, fenofibrate, the NUS study, in which 376 patients with atherosclerosis and neurological symptoms were treated for two years, suggested a superiority for the statin in reducing progression of carotid atherosclerosis [Skoloudik, D. et al., Abst 1055].
Ezetimibe, a cholesterol absorption inhibitor, has been extensively studied as a complement to statins to maximize effect without the need for very high doses of statins. Used in monotherapy, ezetimibe was reported to offer a cost-effective alternative for patients with high LDL-cholesterol levels and a history of cardiovascular disease who could not tolerate statins [Ara, R.M. et al., Abst 1200].
Observations from a randomized trial in 67 patients with type 2 diabetes suggested that vitamin C is effective in elevating HDL-cholesterol levels, but other choices could be superior in patients with more profound dyslipidemia or alterations other than low HDL-cholesterol levels [Siavash, M. et al., Abst 1022]. Regarding other dietary approaches to dyslipidemia, the positive effects of olive oil on HDL-cholesterol were accompanied by improvements in chronic constipation, and increases in triglycerides and albumin in subjects with chronic kidney disease, whereas older individuals without kidney disease showed a decrease in triglycerides [Villarrubia, V.G. et al., 1060].
Other observations discussed during the meeting in Prague included a report in five male individuals aged 40-50 years, in which severe dyslipidemia was markedly improved by Ayurvedan medicine based on Indukantha ghritham (medicated ghee preparation) plant extracts followed by Balaswagandhadi thailam (oil) massage and steam bath [Shetty, A.B. & Roy, P.K., Abst 1151]. Improvements in the lipid profile in the experimental arena were reported with apple pectin fiber [Sandhez, D. et al., Abst 1195]. As an additional curiosity, pearl powder was suggested effective in preventing stroke through an effect on cholesterol accumulation in the vascular wall and antiaging activity [Wang, C.K. & Hsiao, S.C., Abst 1148].
Insulin remains the mainstay in the treatment of type 1 diabetes, and insulin counseling was related with maintained benefits to patients [Laisiriraungrai, M. et al., Abst 1219]. New insulin formulations for oral administration have demonstrated superiority over subcutaneous treatment regarding glycemic control, as reflected by glycosylated hemoglobin levels [Guevara-Aguirre, J. et al., Abst 1201]. Furthermore, lunchtime oral insulin added to basal insulin glargine and prebreakfast and predinner regular insulin facilitated treatment in type 1 diabetic adolescents, resulting in high compliance rates [Guevarra-Aguirre, J. et al., Abst 1203].
Although largely effective in improving glycemic control and insulin sensitivity, thiazolidinediones have been related to edema and an increased risk of congestive heart failure. Such adverse event was prevented by amiloride in five type 2 diabetic individuals with metabolic syndrome [Kuan, P.L. et al., Abst 1049]. Among the thiazolidinediones, pioglitazone offered nonsignificant improvements in lipid levels compared to metformin, although metformin was associated with an increased risk of hypertension in the ANSWER trial [Pandhi, P. et al., Abst 1191]. However, pioglitazone resulted in a more pronounced shift towards larger LDL particles compared to rosiglitazone in nine patients with type 2 diabetes included in a crossover trial [Berneis, K. et al., Abst 1041]; in the experimental arena, pioglitazone was also demonstrated to prevent diabetes-associated cognitive deficit in animals [Kuhad, A. & Chopra, K., Abst 1157]. Furthermore, while data suggesting an infarct size-limiting effect of pioglitazone has been suggested by a number of observations, which was reported to be endothelial and inducible nitric oxide synthase-independent [Birnbaum, Y. et al., Abst 1007], glibenclamide, but not glimepiride was demonstrated to antagonize such effect of pioglitazone in experimental animals [Ye, Y. et al., Abst 1008].
New approaches to the treatment of diabetes are been investigated, including new drugs and new drug administration modalities. In this latter case, pharmacokinetic assessments suggested promise for a metformin gum as an alternative delivery method for the biguanide [Guevara-Aguirre, J. et al., Abst 1030].
Regarding novel therapies and therapeutic targets, observation in experimental models revealed antidiabetic and hypolipidemic potential for a hexane extract of Laportea ovalifolia [Momo Noumessing, E.C. et al., Abst 1106], while the hypoglycemic activity of Artemisia aucheri was documented in streptozotocin-induced diabetic animal models [Eidi, A. et al., Abst 1138] and ethanolic Coriandrum sativum extracts improved insulin release and decreased glucose levels in the same animal model [Eidi, M. et al., Abst 1140]. Generalized antidiabetic properties (lowering of glucose, triglyceride, cholesterol, uric acid, creatinine and aspartate and alanine amino transferase levels) were also attributed to Olea europaea leaves, which in animal were superior to those of glibenclamide [Fallahyan, F. et al., Abst 1164]. In that respect, oleic acid showed protective activity against cardiovascular complications in experimentally diabetic animals [Emekli-Alturfan, E. et al., Abst 1172]. While the glycemic response-modulating effects of barley kernel were also investigated [Abdel-Aal, E.S. et al., Abst 1122], Eucommia ulmoides stimulated glucose uptake by cultured skeletal muscle cells, an effect that could also contribute to glucose homeostasis [Jung, K.H. et al., Abst 1128].
Antiplatelet agents play a major role in the treatment and prevention of cardiovascular events, including stroke, as exemplified by the benefits of aspirin/dipyridamole in preventing repeat strokes and improving cerebral hemodynamics [Kuznetsova, S.M., Abst 1135], but resistance to aspirin and clopidogrel has been described in a significant proportion of patients [Feher, G. et al., Abst 1075; Feher, G. et al., Abst 1076; Pusch, G. & Feher, G., Abst 1231; Pusch, G. & Feher, G., Abst 1232]. A significant reduction in the recurrence rates of cerebral infarction was noted after treatment with cilostazol compared to placebo in 1,052 patients with diabetes and a history of noncardioembolic cerebral infarction [Shinohara, Y., Abst 1065] (Fig. 5). Experimentally, antiplatelet effects and antioxidant activity were described for a series of 4-hydroxycoumarin derivatives of warfarin [Feher, G. et al., Abst 1073]. Similarly, antiplatelet activity and inhibition of oxidative stress was reported with a number of novel poly(ADP-ribose) polymerase inhibitors [Feher, G. et al., Abst 1074]. Rosemary and thyme were shown to inhibit experimental thrombosis without prolonging bleeding time [Yamamoto, J. et al., Abst 1061]. In vitro antiplatelet activity was evidenced with garlic-based products, suggesting that regular consumption of garlic may reduce the incidence of cardiovascular disease [Rahman, K. et al., Abst 1183].
Fig. 5. Cerebral infarction rates in diabetic stroke patients treated with cilostazol or placebo [Shinohara, Y., Abst 1065].
In addition to the above clinical and experimental results, observations in 40 patients with atrial fibrillation with or without history of cerebral ischemic stroke suggested favorable impact of oral anticoagulation in preventing vascular cognitive impairment [Buraga, I. et al., Abst 1108]. However, warfarin-induced intracerebral hemorrhage remains common despite improvements in medical care [Asbury, K.L. et al., Abst 1174].
Although effective in reducing body weight, sibutramine was associated with adverse effects on diastolic blood pressure even when used at low doses for short periods of time [Somes, G.W. et al., Abst 1054] (Fig. 6). On the other hand, results from a randomized, placebo-controlled trial in 25 obese individuals revealed the safety and efficacy in weight reduction of fenugreek galactomannan [Ngondi Judith, L. & Oben Enyong, J., Abst 1100], while fenugreek-phaseolamin-containing chocolate offered benefits on glucose, triglycerides and total, LDL- and HDL-cholesterol [Oben Enyong, J. & Ngondi Judith, L., Abst 1102].
Fig. 6. Systolic and diastolic blood pressure during 12 months of treatment with sibutramine or placebo (patients with blood pressure changes were referred for therapy) [Somes, G.W. et al., Abst 1054].
Regarding dietary approaches, adherence to a fruits-and-dairy pattern was associated with lower risks of metabolic syndrome compared to alternative diet styles, including Korean traditional, alcohol-and-meat and sweets-and-fast food, in a cohort of 406 Korean adults [Shin, S. et al., Abst 1131]. In the same country, compliance with dietary guidelines was associated with a reduced risk for dyslipidemia [Park, E.Y. et al., Abst 1132].
Milk fermented with Lactobacillus helveticus CMA was shown to prevent atherosclerosis in apolipoprotein E-deficient animals through upregulation of antioxidant and downregulation of vasoconstrictive and inflammatory cytokine expression [Akagiri, S. et al., Abst 1078]. In hyperlipidemic animals, supplementation with magnolol (from Magnolia officinalis) suppressed oxidative stress, lowered LDL- and total cholesterol levels and inhibited adhesion molecule-mediated cell adhesion to the aorta, suggesting potential in the treatment of atherosclerosis [Chang, W.C. & Yu, Y.M., Abst 1086]. Attenuation of adhesion molecule expression was reported with carnosic acid, an antioxidant polyphenol produced by Salvia officinalis and Rosmarinus officinalis, also suggesting potential in the prevention and treatment of atherosclerosis [Wu, W.C. & Yu, Y.M., Abst 1085]. Inhibition of atherosclerosis development in apolipoprotein E-knockout animal models was demonstrated with 3-(4’hydroxyl-3’,5’-dimethoxyphenyl)-propionic acid [Noh, J.S. et al., Abst 1216].
Regarding antiinflammatory and antioxidative therapies, water-soluble extracts of Raphanus sativus protected against radical oxidative damage in in vitro tests [Choi, J.S. et al., Abst 1218]. The antioxidant activity of tocotrienol was related to the effect of the compound in suppressing cyclooxygenase 2 [Wada, S. et al., Abst 1077]. A Chinese herbal product, Braintone (Rhodiola sp., Panax notoginseng, Ligusticum sinense and Ginkgo biloba), offered benefits in stroke animal models that were related to antioxidant activity [Loh, K.P. et al., Abst 1255].
Education was considered highly important for stroke prevention, to identify and control modifiable risk factors according to each patient’s age and risk profile [Spencer, A.S., Abst 1023]. In that respect, a school-based health promotion program among adolescents was effective in controlling dietary and physical activity-related risk factors for obesity [Azadi, A. et al., Abst 1039]. In a similar way, family health counseling in hypertensive women was able to lower blood pressure values [Jafari, N. et al., Abst 1040], while group discussion with high-school students also led to blood pressure reductions in their parents [Azati, A. et al., Abst 1038]. As a complement, a study in 383 patients not at goal while not receiving thiazide diuretics, or at goal on a calcium channel blocker, who were randomized to active patient inquiry with a physician about thiazides demonstrated that patient-initiated overt discussion of thiazides with a health care provider resulted in increased rates of thiazide initiation in subjects not controlled with other medications, as well as an overall positive effect on blood pressure control [Carter, B.L. et al., Abst 1058]. On the contrary, discontinuation of physician/pharmacist collaboration resulted in deterioration of blood pressure in 63 patients [Carter, B. et al., Abst 1051].
Education and nutritional management had even greater importance in patients with diabetes, in which food guidance was described as highly important for preventing comorbidities [Sachs, A. et al., Abst 1050], and a diabetes self-management program was able to improve both glycemic control and quality of life in 147 patients, resulting in reduced stroke events compared to control subjects [Wattana, C. et al., Abst 1072].
Other examples of the benefits of education aimed at lifestyle modification were reported during the meeting, including the CHAP program, in which community-wide programs to promote awareness on cardiovascular disease yielded community mobilization and improved control of blood pressure, glycemia, lipids and smoking [Chambers, L.W. et al., Abst 1149; Karwalajtys, T. et al., Abst 1155].
Myoinositol was noted to prevent kainite- and pentylenetetrazole-induced seizures in experimental animals [Nozadze, M. et al., Abst 1044].
Premna oblongifolia leaves were suggested as fermentable dietary fiber based on studies in experimental animals [Nurdin, S.U., Abst 1047; Nurdin, S.U., Abst 1048].
Influenza vaccination had no impact on vascular outcomes in 282 patients included in an observational case-control study [Luengo, J. et al., Abst 1037].
Citicoline showed cognitive function-improving activity in post-stroke dementia patients [Shanmugam, S., Abst 1152].
Thioredoxin-mediated neuroprotective effects of estradiol were shown in experimental animal studies [Chen, T.Y. et al., Abst 1181].
Red wine demonstrated antiarrhythmic activity comparable to propafenone after ischemia-reperfusion injury, and attenuated lactate dehydrogenase release [Lunder, M. et al., Abst 1217].
Report prepared by: X. Rabasseda, Prous Science Medical Information Department