Effect of Pioglitazone and Ramipril on Biomarkers of Low-Grade Inflammation and Vascular Function in Nondiabetic Patients with Increased Cardiovascular Risk and an Activated Inflammation: Results from the PIOace Study
Free accessResearch articleFirst published online July, 2011
Effect of Pioglitazone and Ramipril on Biomarkers of Low-Grade Inflammation and Vascular Function in Nondiabetic Patients with Increased Cardiovascular Risk and an Activated Inflammation: Results from the PIOace Study
This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk.
Methods and Results:
Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m2, duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (−0.89 ± 1.98 mg/liter; −25%) and PIRA (−0.49 ± 2.11 mg/liter; −16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: −0.78 ± 1.39 (−29%)/0.15 ± 1.03 (+5%)/ −1.44 ± 2.83 (−40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metalloproteinase-9: −48 ± 127 (−12%)/−1 ± 224 (0%)/−60 ± 210 ng/ml (−13%), p < .05 for RAM vs PIO or PIRA in all cases].
Conclusions:
Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials.
MeigsJB. Epidemiology of the metabolic syndrome. Curr Diab Rep. 2003; 3 (1): 73–9.
2.
German Diabetes Association, MatthaeiSBierwirthRFritscheAGallwitzBHäringHUJoostHGKellererMKloosChKuntTNauckMSchernthanerGSiegelEThienelF. Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association. Exp Clin Endocrinol Diabetes. 2009; 117 (9): 522–57.
3.
Van GaalLFMertensLDe BlockCE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006; 444: 875–80.
4.
ForstTHohbergCPfütznerA. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetes patients. Horm Metab Res. 2009; 41 (2): 123–31.
5.
BergmanRNKimSPHsuIRCatalanoKJChiuJDKabirMRicheyJMAderM. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Am J Med. 2007; 120 (Suppl 1): S3–8.
6.
RitchieSAConnellJM. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis. 2007; 17 (4): 319–26.
7.
RosenEDSpiegelmanBM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006; 444 (7121): 847–53.
HanefeldM. Postprandial hyperglycemia: noxious effects on the vessel wall. Int J Clin Pract Suppl. 2002; 129: 45–50.
10.
HomeP. Contribution of basal and post-prandial hyperglycemia to micro- and macrovascular complications in people with type 2 diabetes. Curr Res Med Opin. 2005; 21 (7): 989–98.
11.
DeFronzoRATripathyDSchwenkeDCBanerjiMBrayGABuchananTAClementSCHenryRRHodisHNKitabchiAEMackWJMudaliarSRatnerREWilliamsKStentzFBMusiNReavenPD; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011; 364 (12): 1104–15.
12.
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, GersteinHCYusufSBoschJPogueJSheridanPDinccagNHanefeldMHoogwerfBLaaksoMMohanVShawJZinmanBHolmanRR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006; 368 (9541): 1096–105. Erratum in: Lancet. 2006;368(9549):1770.
13.
YusufSSleightPPogueJBoschJDaviesRDagenaisG. Effects of an angiotensin-converting-enzyme inihibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342 (3): 145–53.
14.
DREAM Trial Investigators. BoschJYusufSGersteinHCPogueJSheridanPDagenaisGDiazRAvezumALanasFProbstfieldJFodorGHolmanRR. The effect of ramipril on the incidence of diabetes. N Engl J Med. 2006; 355 (15): 1551–62.
15.
HanefeldMMarxNPfütznerABaurechtWLübbenGKargiannisEStierUForstT. Anti-inflammatory effect of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol. 2007; 49 (3): 290–7.
16.
MatthewsDRHoskerJPRudenskiASNaylorBATreacherDFTurnerRC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28 (7): 412–9.
17.
HedbladBNilssonPJanzonLBerglundG. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden. Diabet Med. 2000; 17 (4): 299–307.
18.
PfütznerAForstT. High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diab Technol Ther. 2006; 8 (1): 28–36.
19.
LangenfeldMRForstTHohbergCKannPLübbenGKonradTFüllertSSacharaCPfütznerA. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation. 2005; 111 (19): 2525–31.
20.
MazzoneTMeyerPMFeinsteinSBDavidsonMHKondosGTD'AgostinoRBSrPerezAProvostJCHaffnerSM. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006; 296 (21): 2572–81.
21.
ForstTWilhelmBPfütznerAFuchsWLehmannUSchaperFWeberMMüllerJKonradTHanefeldM. Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk. Diab Vasc Dis Res. 2008; 5 (4): 298–303.
22.
NissenSENichollsSJWolskiKNestoRKupferSPerezAJureHDe LarochellièreRStaniloaeCSMavromatisKSawJHuBLincoffAMTuzcuEM; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008; 299 (13): 1561–73.
23.
PfütznerAMarxNLübbenGLangenfeldMWalcherDKonradTForstT. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol. 2005; 45 (12): 1925–31.
24.
HamannAGarcia-PuigJPaulGDonaldsonJStewartM. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone. Exp Clin Endocrinol Diabetes. 2008; 116 (1): 6–13.
25.
KaragiannisEPfütznerAForstTLübbenGRothWGrabellusMFlanneryMSchöndorfT. The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions. Diabetes Technol Ther. 2008; 10 (3): 206–12.
26.
KatoTSawaiYKanayamaHTaguchiHTerabayashiTTakiFYamadaKYamazakiYHayakawaNSuzukiAOdaNKatadaNItohM. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes. 2009; 117 (10): 593–9.
27.
ForstTKaragiannisELübbenGHohbergCSchöndorfTDiktaGDrexlerMMorcosMDänschelWBorchertMPfütznerA. Pleiotrophic and anti-inflammatory effects of pioglitazone precede the metabolic activity in type 2 diabetic patients with coronary artery disease. Atherosclerosis. 2008; 197 (1): 311–7.
28.
DormandyJACharbonnelBEcklandDJErdmannEMassi-BenedettiMMoulesIKSkeneAMTanMHLefèbvrePJMurrayGDStandlEWilcoxRGWilhelmsenLBetteridgeJBirkelandKGolayAHeineRJKorányiLLaaksoMMokánMNorkusAPiragsVPodarTScheenAScherbaumWSchernthanerGSchmitzOSkrhaJSmithUTatonJ; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366 (9493): 1279–89.
29.
ErdmannEDormandyJACharbonnelBMassi-BenedettiMMoulesIKSkeneAM; PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007; 49 (17): 1772–80.
30.
WilcoxRBousserMGBetteridgeDJSchernthanerGPiragsVKupferSDormandyJ. PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke. 2007; 38 (3): 865–73.
31.
ForstTPfütznerALübbenGWeberMMarxNKaragiannisEKöhlerCBaurechtWHohbergCHanefeldM. Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk—the PIOSTAT Study. Metabolism. 2007; 56 (4): 491–6.
32.
ScheenAJ. Prevention of type 2 diabetes through inhibition of the renin-angiotensin system. Drugs. 2005; 64 (22): 2537–65.
GilesTDSanderAG. Effects of thiazolidinediones on blood pressure. Curr Hypertens Rep. 2007; 9 (4): 332–7.
35.
AnanFMasakiTFukunagaNTeshimaYIwaoTKanedaKUmenoYOkadaKWakasugiKYonemochiHEshimaNSaikawaTYoshimatsuH. Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus. Eur J Clin Invest. 2007; 37 (9): 709–14.
36.
SchöndorfTForstTHohbergCPahlerSLinkCRothWPfütznerA. The IRIS III study: pioglitazone improves metabolic control and blood pressure in patients with type 2 diabetes without increasing body weight. Diab Obes Metab. 2007; 9 (1): 132–3.
37.
CicconettiPDonadioCPazzagliaMCD'AmbrosioFMariglianoV. [Circadian rhythm of blood pressure: non-dipping pattern and cardiovascular risk][Article in Italian]. Recenti Prog Med. 2007; 98 (7–8): 401–6.
38.
ZweikerREberBSchumacherMToplakHKleinW. “Non-dipping” related to cardiovascular events in essential hypertensive patients. Acta Med Austriaca. 1994; 21 (3): 86–9.
39.
KonesR. Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease—a perspective. Drug Des Devel Ther. 2010; 4: 383–413.
