RESUMEN
BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.
Asunto(s)
Complicaciones de la Diabetes/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Riñón/efectos de los fármacos , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Análisis de Varianza , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Atorvastatina , Creatinina/orina , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Europa (Continente) , Fluorobencenos/farmacología , Ácidos Heptanoicos/farmacología , Humanos , Lípidos/sangre , América del Norte , Proteinuria , Pirimidinas/farmacología , Pirroles/farmacología , Rosuvastatina Cálcica , América del Sur , Sulfonamidas/farmacologíaRESUMEN
The role of the Renin-Angiotensin-Aldosterone system (RAAS) on the development of insulin resistance and cardiovascular disease is an area of growing interest. Most of the deleterious actions of the RAAS on insulin sensitivity appear to be mediated through activation of the Angiotensin II (Ang II) Receptor type 1 (AT(1)R) and increased production of mineralocorticoids. The underlying mechanisms leading to impaired insulin sensitivity remain to be fully elucidated, but involve increased production of reactive oxygen species and oxidative stress. Both experimental and clinical studies also implicate aldosterone in the development of insulin resistance, hypertension, endothelial dysfunction, cardiovascular tissue fibrosis, remodelling, inflammation and oxidative stress. There is abundant evidence linking aldosterone, through non-genomic actions, to defective intracellular insulin signalling, impaired glucose homeostasis and systemic insulin resistance not only in skeletal muscle and liver but also in cardiovascular tissue. Blockade of the different components of the RAAS, in particular Ang II and AT(1)R, results in attenuation of insulin resistance, glucose homeostasis, as well as decreased cardiovascular disease morbidity and mortality. These beneficial effects go beyond to those expected with isolated control of hypertension. This review focuses on the role of Ang II and aldosterone in the pathogenesis of insulin resistance, as well as in clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and cardiovascular disease.
Asunto(s)
Aldosterona/metabolismo , Angiotensina II/metabolismo , Resistencia a la Insulina , Aldosterona/genética , Angiotensina II/genética , Animales , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Metabólicas/metabolismo , Sistema Renina-AngiotensinaRESUMEN
There is a worldwide pandemic of type 2 diabetes mellitus (DM) that is projected to further increase in the next several decades, due in part to aging and increasing obesity. DM and hypertension are chronic conditions that very frequently coexist in older subjects and both conditions are strongly predisposing factors to the development of cardiovascular disease (CVD) and of renal damage with enormous economic and social burden to all countries. Currently, there is clear-cut evidence that the tight control of high blood pressure and associated risk factors such as hyperglycemia and dyslipidemia reduce the burden of CVD and renal disease in patients with DM. ln addition, the control of systolic blood pressure, especially in older patients, reduces the risk of stroke and other CVO events. Non-pharmacological treatment with appropriate diet and exercise program is an important component of therapy in persons with established diabetes. However, a non-pharmacological approach is often not enough to achieve desirable blood pressure values goals; in this regard pharmacological strategies that block the renin-angiotensin system (RAS) have special benefits in diabetic hypertensive patients and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. The use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor-blocking agents (ARBs), besides blood pressure control, decrease the rate of development of proteinuria and diabetic nephropathy. Therefore, an aggressive control of blood pressure to values below 130/80 has an important impact on the complications of type 2 DM