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Abstract Recommendations and guidelines propose to com bine antihypertensive drugs to improve BP control, highlighting the advantages of single-pill combinations (SPCs) to improve treatment adherence. It is speculated that, compared with free-dose combinations (Free-DCs), SPC should achieve a reduction in cardiovascular (CV) events and mortality through better adherence and BP control. However, there is little information in this regard. For this reason, the objective of this review was to provide a descriptive analysis the differences in CV outcomes between SPCs antihypertensive drugs treat ments vs. Free-DCs treatments. Ten studies were found and none had a randomized controlled design. Medi cation adherence was higher with SPCs, but outcomes were not adjusted for the adherence/persistence. When groups were compared according to similar adherence degrees, the statistical significance in favor of SPCs disappeared. Thus, randomized controlled studies are necessary to evaluate if SPCs have any effect beyond the improvement of the adherence to hypertensive treatment.

Resumen Las recomendaciones y las guías proponen combinar fármacos antihipertensivos para mejorar el control de la presión arterial, destacando las ventajas de las combi naciones en un solo comprimido para mejorar la adhe rencia al tratamiento. Se especula que, en comparación con las combinaciones en varios comprimidos, deberían lograr una reducción de los eventos cardiovasculares y de la mortalidad a través de una mejor adherencia y con trol de la presión. Sin embargo, hay poca información al respecto. Por esta razón, el objetivo de esta revisión fue proporcionar un análisis descriptivo de las diferencias en los resultados cardiovasculares y la mortalidad entre los tratamientos con combinaciones de antihipertensi vos en un solo comprimido vs. combinaciones de los mismos grupos de fármacos en varios comprimidos. Se encontraron diez estudios, pero ninguno tenía un dise ño controlado aleatorio. La adherencia a la medicación fue mayor con las combinaciones en un comprimido, pero los resultados no se ajustaron por la adherencia/ persistencia. Cuando se compararon los grupos según grados de adherencia similares, la significación estadís tica a favor de las combinaciones en un comprimido se perdió. Por lo tanto, son necesarios estudios controlados aleatorios para evaluar si las combinaciones de antihi pertensivos en un comprimido tienen algún efecto más allá de la mejora de la adherencia al tratamiento.

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Background and objectiveEfficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin–angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients.MethodsWe searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords.“Renal Insufficiency, Chronic” or “Diabetic Nephropathies” and “Sodium-glucose cotransporter 2 inhibitors”. We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337.ResultsTen RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66–0.91, p=0.002; RR=0.7, 95% CI: 0.61–0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=−0.19, 95% CI: −0.24 to −0.14; RR=0.61, 95% CI: 0.51–0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59–0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=−5.4, 95% CI: −7.24 to −3.57), this effect was reversible. (AU)

Antecedentes y objetivosLa eficacia de los inhibidores del cotransportador de sodio-glucosa 2 (SGLT2) en combinación con los bloqueadores del sistema renina-angiotensina (SRA) para la enfermedad renal crónica (ERC) sigue siendo controvertida. Se realizó este metaanálisis para explorar el efecto de los inhibidores del SGLT2 en combinación con los bloqueadores del SRA sobre los resultados cardiovasculares en los pacientes con ERC.MétodosSe realizaron búsquedas en las bases de datos Embase, PubMed, Web of Science y Cochrane Library con las siguientes palabras clave: «Renal Insufficiency, Chronic» o «Diabetic Nephropathies» y «Sodium-glucose cotransporter 2 inhibitors». Se incluyeron ensayos controlados aleatorios (ECA) basados en el tratamiento con inhibidores de la enzima convertidora de angiotensina (IECA) o bloqueadores de los receptores de la angiotensina II (BRA). Los eventos de resultado incluyeron resultados cardíacos y renales y otros eventos adversos. Este estudio está registrado en PROSPERO: CRD42020218337.ResultadosDiez ECA que incluían 16.983 pacientes con ERC cumplieron los criterios de inclusión. En comparación con el placebo más bloqueadores del SRA, los inhibidores de SGLT2 más bloqueadores del SRA redujeron significativamente la mortalidad cardiovascular y las tasas de hospitalización relacionadas con la insuficiencia cardíaca (RR=0,78; IC del 95%: 0,66 a 0,91; p=0,002; RR=0,7; IC del 95%: 0,61 a 0,8; p=0,000). También se realizó un análisis secuencial de ensayos (TSA) y los resultados indicaron que nuestros resultados son fiables. (AU)

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BACKGROUND AND OBJECTIVE: Efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin-angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. METHODS: We searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords. "Renal Insufficiency, Chronic" or "Diabetic Nephropathies" and "Sodium-glucose cotransporter 2 inhibitors". We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. RESULTS: Ten RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66-0.91, p=0.002; RR=0.7, 95% CI: 0.61-0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=-0.19, 95% CI: -0.24 to -0.14; RR=0.61, 95% CI: 0.51-0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59-0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=-5.4, 95% CI: -7.24 to -3.57), this effect was reversible. CONCLUSIONS: These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.

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