Inhibitory sodíko‑glukózového kotransportéru 2 (SGLT2), jinak též glifloziny, jsou jednou z nových skupin perorálních antidiabetik, která se začala používat před několika lety a dnes již tvoří pevnou součást péče o diabetiky. Glifloziny redukují reabsorpci glukózy v proximálních tubulech v ledvinách, čímž zvyšují exkreci glukózy močí, a tím zlepšují kontrolu glykemie. Pacienty bývají obecně dobře tolerovány, i když se při jejich užívání mohou vzácně vyskytnout závažné nežádoucí účinky a poměr přínos/riziko se mezi jednotlivými glifloziny liší. Přibývají nicméně poznatky, že jejich příznivý účinek se projevuje na více frontách – zejména kardioprotektivně a renoprotektivně. Na Evropském kardiologickém kongresu v září 2019 v Paříži byly prezentovány výsledky studie DAPA‑HF, v níž dapagliflozin prokázal přínos u pacientů se srdečním selháním se sníženou ejekční frakcí levé komory bez ohledu na to, zda trpěli, nebo netrpěli diabetes mellitus 2. typu. Studie přináší nový pohled na využití gliflozinů v léčbě srdečního selhání.

Sodium glucose cotransporter‑2 (SGLT2) inhibitors, also known as gliflozins, are one of the new groups of oral antidiabetics that have been used for several years and currently represent a solid part of care for diabetic patients. Gliflozins reduce reabsorption of glucose in proximal tubules in kidneys that leads to increased excretion of glucose in urine and improved glycaemia control. They are well‑tolerated by patients even though severe adverse effects may rarely arise during their administration; the risk/benefit ratio differs among gliflozins. New findings accumulate that their beneficial effect is multifaceted – especially cardiprotective and renoprotective. At the European Congress of Cardiology in September 2019 in Paris, results of DAPA‑HF study were presented in which dapagliflozin showed benefit in patients with heart failure with reduced ejection fraction of left ventricle regardless of type 2 diabetes mellitus status. The study brings new perspective on gliflozin use in the treatment of heart failure.

• Klíčová slova
• DAPA-HF,
• MeSH
• aplikace orální MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• dysfunkce levé srdeční komory farmakoterapie   MeSH
• glifloziny * aplikace a dávkování   farmakologie   MeSH
• klinická studie jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• riziko MeSH
• senioři MeSH
• srdeční selhání farmakoterapie   MeSH
• statistika jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH

V medicíne dôkazov v oblasti kardiovaskulárnej diabetológie došlo v poslednom období k prudkému rozvoju poznatkov. Celkom posledná realizovaná a nedávno publikovaná štúdia DAPA-HF priniesla odpoveď na nové mechanizmy, ktoré predstavuje liečba inhibítormi SGLT2 nielen u pacientov s diabetes mellitus, ale aj bez tohto ochorenia v skupine pacientov s chronickým srdcovým zlyhávaním so zníženou systolickou funkciou ľavej komory srdca. V predloženom prehľade bude zameraná pozornosť na túto liečbu v kontexte podobných iných randomizovaných klinických štúdií, nakoľko štyri takéto štúdie u pacientov s diabetes mellitus 2 typu preukázali významný preventívny benefit.

Evidence-based medicine in the field of cardiovascular diabetology brought recently new evidences. Last realized and published study DAPA-HF brought the answer concerning new mechanisms with SGLT2 inhibitors among patients not only with diabetes mellitus, but also without diabetes mellitus and heart failure with reduced systolic left ventricular function. Presented review brings its context to other randomized clinical trials, that brought substantial benefit of treatment in patients with diabetes mellitus.

• Klíčová slova
• dapagliflozin, studie DAPA-HF,
• MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glifloziny terapeutické užití   MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• srdeční selhání farmakoterapie   MeSH
• Check Tag
• lidé MeSH

AIMS: The aim of this study was to examine whether left ventricular ejection fraction (LVEF) modified efficacy and safety of dapagliflozin 10 mg compared with placebo in the 4744 patients with LVEF ≤40% randomized in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS: We examined whether LVEF, analysed categorically or continuously, modified the effect of dapagliflozin. The primary efficacy outcome was the composite of a worsening heart failure (HF) event (unplanned HF hospitalization/an urgent HF visit requiring intravenous therapy) or cardiovascular death. Mean LVEF was 31.1% and LVEF categories analysed were: <26% (n = 1143), 26-30% (n = 1018), 31-35% (n = 1187), and >35% (n = 1396). Each 5% decrease in LVEF was associated with a higher risk of the primary outcome [hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.13-1.24]. The benefit of dapagliflozin was consistent across the spectrum of LVEF: the dapagliflozin vs. placebo HR was 0.75 (95% CI 0.59-0.95) for LVEF <26%, 0.75 (0.57-0.98) for LVEF 26-30%, 0.67 (0.51-0.89) for LVEF 31-35%, and 0.83 (0.63-1.09) for LVEF >35% (P for interaction = 0.762). Similarly, the effect of dapagliflozin on the components of the primary endpoint was not modified by baseline LVEF (P for interaction for cardiovascular death = 0.974, and for worsening HF = 0.161). Safety of dapagliflozin was also consistent across the range of LVEF and neither efficacy nor safety were modified by diabetes status. CONCLUSION: Left ventricular ejection fraction was a significant predictor of hospitalization and mortality in patients with HF with reduced ejection fraction but did not modify the beneficial effect of dapagliflozin, overall or separately, in patients with and without diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03036124.

• MeSH
• benzhydrylové sloučeniny terapeutické užití   MeSH
• funkce levé komory srdeční * MeSH
• glukosa MeSH
• glukosidy terapeutické užití   MeSH
• lidé MeSH
• sodík MeSH
• srdeční selhání * farmakoterapie   MeSH
• tepový objem MeSH
• transportér 2 pro sodík a glukózu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

OBJECTIVE: The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial. RESEARCH DESIGN AND METHODS: The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. RESULTS: At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. CONCLUSIONS: In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.

• MeSH
• benzhydrylové sloučeniny terapeutické užití   MeSH
• diabetes mellitus 2. typu * komplikace   farmakoterapie   epidemiologie   MeSH
• glukosidy MeSH
• incidence MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   epidemiologie   MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

• MeSH
• benzhydrylové sloučeniny aplikace a dávkování   MeSH
• diuretika aplikace a dávkování   MeSH
• glukosidy aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční selhání farmakoterapie   patofyziologie   MeSH
• tepový objem účinky léků   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• Publikační typ
• novinové články MeSH
• rozhovory MeSH

• Klíčová slova
• Dapagliflozin (Invokana),
• MeSH
• diabetes mellitus 2. typu farmakoterapie   komplikace   MeSH
• dvojitá slepá metoda MeSH
• glifloziny aplikace a dávkování   farmakologie   MeSH
• hypoglykemika MeSH
• lidé MeSH
• placeba terapeutické užití   MeSH
• srdeční selhání farmakoterapie   mortalita   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• dapagliflozin,
• MeSH
• chronická renální insuficience farmakoterapie   komplikace   MeSH
• diabetes mellitus 2. typu * epidemiologie   prevence a kontrola   MeSH
• glifloziny * aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• riziko MeSH
• senioři MeSH
• srdeční selhání farmakoterapie   komplikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. OBJECTIVE: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DESIGN: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124). SETTING: 410 sites in 20 countries. PATIENTS: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. INTERVENTION: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MEASUREMENTS: The primary outcome was worsening HF or cardiovascular death. RESULTS: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. LIMITATION: Enrollment criteria precluded the inclusion of very high-risk patients. CONCLUSION: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. PRIMARY FUNDING SOURCE: AstraZeneca.

• MeSH
• benzhydrylové sloučeniny MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• dysfunkce levé srdeční komory * MeSH
• funkce levé komory srdeční MeSH
• glukosidy MeSH
• křehkost * komplikace   MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH