Protección cardiovascular de los nuevos antidiabéticos efecto de clase? Sí, el efecto CV de los nuevos antidiabéticos son comunes a los fármacos de una misma familia Dr E.Rovira Unidad HTA. Hospital de La Ribera.
Excreción urinaria de glucosa inhibición SGLT2 Filtered glucose load > 180 g/day SGLT2 SGLT1 SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to urinary glucose excretion * and osmotic diuresis Bakris et al. Kidney Int 2009;75;1272 7. 2
Propiedades farmacológicas Therapeutic dose (mg/day) Starting dose Administration Empagliflozin Dapagliflozin Canagliflozin 10 25 10 QD With or without food 5 10 10 QD With or without food 100 300 100 QD Before first meal Peak plasma concentration (hours post-dose) 1.5 Within 2 1 2 Absorption (mean oral bioavailability) Metabolism Elimination (half-life, hours) 60% ~ 78% ~ 65% Hepatic:renal 43:57 [12.4] Primarily glucuronidation - no active metabolite Hepatic:renal 22:78 [12.9] Hepatic:renal 67:33 [13.1]* Selectivity over SGLT1 1:5000 > 1:1400 > 1:160 1 Glucose excretion with higher dose (g/day) 78 ~ 70 119 *For the 300 mg dose. Data from http://www.ema.europa.eu/ (Jardiance SPC, Forxiga SPC, Invokana PI, Invokana SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188 97. 3
Inhibición de SGLT2 modula factores relacionados con el riesgo cardiovascular Novel Pathways (?) Blood pressure Arterial stiffness Albuminuria SNS activity SNS (?) activity (?) Glucose Insulin Uric Acid Weight Visceral adiposity Oxidative stress LDL-C HDL-C Triglycerides Inzucchi et al. Diab Vasc Dis Res 2015;12:90 100.
Eficacia similar entre SGLT2 Hb A1c Peso BMC Endocr Disord 2013 Dec 17;13:58.
Ensayos de seguridad cardiovacular EMPA-REG CANVAS OUTCOME 1 2 CANVAS-R 3 CREDENCE 4 DECLARE- TIMI 58 5 Ertugliflozin CVOT 6 Interventions Main inclusion criteria Empagliflozin/ placebo Est. vascular complications Canagliflozin/ placebo Est. vascular complications or 2 CV risk factors Canagliflozin/ placebo Est. vascular complications or 2 CV risk factors Canagliflozin/ placebo Stage 2 or 3 CKD + macroalbuminuria Dapagliflozin/ placebo High risk for CV events Ertugliflozin/ placebo Est. vascular complications No. of patients 7034 4339 5700 3627 17,150 3900 Primary outcome Key secondary outcome Target no. of events Estimated median FU Estimated completion 3P-MACE 3P-MACE Progression of albuminuria 4P-MACE Fasting insulin secretion, progression of albuminuria Regression of albuminuria, change in egfr ESKD, S-creatinine doubling, renal/cv death 4P-MACE + HHF 3P-MACE 4P-MACE + HHF + revascularisation 3P-MACE 4P-MACE 691 420 TBD TBD 1390 TBD ~3 years 6 7 years 3 years ~4 years 4 5 years 5 7 years 2015 Apr 2017 2017 2019 2019 2021 Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90 100. 1. Zinman et al. Cardiovasc Diabetol 2014;13:102. 2. NCT01032629. 3. NCT01989754. 4. NCT02065791. 5. NCT01730534. 6. NCT01986881.
EMPA-REG OUTCOME : Criterios de inclusión Adults with insufficient glycaemic control Age 18 years HbA 1c o 7% and 10% if on background glucoselowering therapy, or o 7% and 9% if drug-naïve BMI 45 kg/m 2 High risk of CV events ( 1 of the following) History of MI (> 2 months prior to enrolment) Evidence of single/multi-vessel CAD Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CAD History of stroke (ischaemic or haemorrhagic) > 2 months prior to consent Occlusive peripheral artery disease Zinman et al. Cardiovasc Diabetol 2014;13:102. 8
EMPA-REG OUTCOME : Resultados
Efecto cardiovascular de canagliflozina Metaanálisis http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Public_assessment_report/human/002649/WC500156457.pdf.
Efecto cardiovascular de dapagliflozina Metaanálisis Sonesson et al. Cardiovasc Diabetol (2016) 15:37
Tratamiento en Diabetes tipo 2 American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1): SX
CONCLUSIONES Mismo mecanismo acción y similar farmacocinética. Similar eficacia sobre glucemia, peso, PA y colesterol. Sobre seguridad cardiovascular: Falta de evidencia con cana y dapagliflocina. Necesidad de confirmar con empagliflocina Efecto en prevención primaria y sobre otras poblaciones