Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 87
Filtrar
1.
Kidney Int ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181154

RESUMO

Treatment with sodium-glucose co-transporter-2 inhibitors induces an initial 3-5 ml/min/1.73 m2 decline in estimated glomerular filtration rate (eGFR). Although considered to be of hemodynamic origin and largely reversible, this 'eGFR dip' may cause concern in clinical practice, which highlights the need to better understand its incidence and clinical implications. In this post hoc analysis of the EMPA-REG OUTCOME trial, 6,668 participants randomized to empagliflozin 10 mg, 25 mg or placebo with eGFR available at baseline and week four were categorized by initial eGFR change into three groups; over 10% decline ('eGFR dipper'), over 0 and up to 10% decline ('eGFR intermediate'), no eGFR decline ('eGFR non-dipper'). Baseline characteristics of 'eGFR intermediate' and 'eGFR non-dipper' were generally comparable. An initial 'eGFR dip' was observed in 28.3% of empagliflozin versus 13.4% of placebo-treated participants; odds ratio 2.7 [95% Confidence Interval 2.3-3.0]. In multivariate logistic regression, diuretic use and higher KDIGO risk category at baseline were independently predictive of an 'eGFR dip' in empagliflozin versus placebo. Safety and beneficial treatment effects with empagliflozin on cardiovascular and kidney outcomes were consistent across subgroups based on these predictive factors. The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease. Thus, patients with type 2 diabetes with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of over 10% with empagliflozin, but reduction in cardiovascular and kidney outcomes was not relevantly modified by such 'eGFR dip'.

2.
Lancet Diabetes Endocrinol ; 8(12): 949-959, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33217335

RESUMO

BACKGROUND: Patients with type 2 diabetes and atherosclerotic cardiovascular disease are at high clinical risk. We assessed the effect of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on total cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial. METHODS: The EMPA-REG OUTCOME trial was a randomised, double-blind, non-inferiority trial of patients (aged ≥18 years) with type 2 diabetes and atherosclerotic cardiovascular disease done between August, 2010, and April, 2015. Participants were randomly assigned (1:1:1) to empagliflozin 10 mg or 25 mg, or placebo. The primary outcome was major adverse cardiovascular events: a composite of cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction. As prespecified, the effects of pooled empagliflozin versus placebo were assessed on total (first plus recurrent) events of major adverse cardiovascular events, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, and admission to hospital for heart failure. We also did post-hoc analyses on additional cardiovascular and admission to hospital outcomes. We used statistical models that preserve randomisation and account for correlation of recurrent events, including negative binomial regression, as prespecified for the primary analyses. The EMPA-REG OUTCOME trial is registered with ClinicalTrials.gov, NCT01131676, and is closed to accrual. FINDINGS: In the EMPA-REG OUTCOME trial, 7020 patients were randomly assigned and treated with empagliflozin 10 mg (n=2345), empagliflozin 25 mg (n=2342), or placebo (n=2333) and followed up for a median of 3·2 years (IQR 2·2 to 3·6) in the pooled empagliflozin group and 3·1 years (2·2 to 3·5) in the placebo group. Analysing total (first plus recurrent) events, empagliflozin versus placebo reduced the risk of major adverse cardiovascular events (rate ratio [RR] 0·78 [95% CI 0·67 to 0·91]; p=0·0020; 12·88 [95% CI 3·74 to 22·02] events prevented per 1000 patient-years); fatal or non-fatal myocardial infarction (0·79 [0·62 to 0·998]; p=0·049; 4·97 [-0·68 to 10·61] events prevented per 1000 patient-years); the composite of fatal or non-fatal myocardial infarction, or coronary revascularisation (0·80 [0·67 to 0·95]; p=0·012; 11·65 [1·25 to 22·05] events prevented per 1000 patient-years); admission to hospital for heart failure (0·58 [0·42 to 0·81]; p=0·0012; 9·67 [3·07 to 16·28] events prevented per 1000 patient-years); and all-cause admission to hospital (0·83 [0·76 to 0·91]; p<0·0001; 50·41 [26·20 to 74·63] events prevented per 1000 patient-years). For outcomes significantly reduced with empagliflozin, risk reductions were numerically larger for total events than for first events. Total fatal or non-fatal stroke was not significantly different between treatment groups (RR 1·10 [95% CI 0·82 to 1·49]; p=0·52). INTERPRETATION: Empagliflozin reduced the total burden of cardiovascular complications and all-cause admission to hospital in patients with type 2 diabetes and atherosclerotic cardiovascular disease. FUNDING: The Boehringer Ingelheim and Lilly Alliance.

3.
Clin J Am Soc Nephrol ; 15(10): 1433-1444, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32994159

RESUMO

BACKGROUND AND OBJECTIVES: In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc, we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework. RESULTS: Of 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes (P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes (P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category. CONCLUSIONS: The observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: EMPA-REG OUTCOME, NCT01131676.

5.
Diabetes Obes Metab ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32744354

RESUMO

AIM: To explore the cardiovascular (CV) and kidney effects of empagliflozin in patients with different clinical phenotypes of diabetic kidney disease (DKD) (i.e. with the presence or absence of overt albuminuria) participating in the EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME randomized participants (1:1:1) to empagliflozin 10 mg, 25 mg or placebo, added to standard of care. Post hoc, patients with different clinical phenotypes of DKD at baseline were categorized in three subgroups: (a) overt DKD (overt albuminuria [urinary albumin-to-creatinine ratio of >300 mg/g] with any estimated glomerular filtration rate [eGFR]; n = 769); (b) non-overt DKD (kidney impairment [eGFR < 60 mL/min/1.73 m2 ] without overt albuminuria [urinary albumin-to-creatinine ratio of ≤300 mg/g]; n = 1290); and (c) 'all others' (eGFR ≥ 60 mL/min/1.73 m2 without overt albuminuria; n = 4893). Analyses included CV (death, hospitalization for heart failure, all-cause hospitalization) and selected kidney outcomes, change in eGFR and kidney safety. Cox proportional hazards models assessed the consistency of treatment effect across subgroups. RESULTS: Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (P-values for interaction >.05), consistent with the overall trial population findings. Empagliflozin also significantly reduced the yearly loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups. CONCLUSIONS: Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical form, both with or without the presence of overt albuminuria.

8.
JAMA ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536101

RESUMO

Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT01243424.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31495881

RESUMO

BACKGROUND: Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints. METHODS: The study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676). RESULTS: Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold. CONCLUSIONS: The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.

10.
Diabetes Obes Metab ; 21(11): 2465-2473, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31297968

RESUMO

AIM: To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy. MATERIALS AND METHODS: This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged ≥60 years and body mass index ≤45 kg/m2 . HbA1c and fasting plasma glucose were measured at study visits, and participants assessed glycaemic control with a self-monitoring blood glucose device. Adverse events (AEs) were reported during the study. RESULTS: Three hundred and two participants were randomized 1:1 to linagliptin 5 mg qd and placebo, with one third of patients from Japan. Study population age and HbA1c (baseline mean ± SD) were 72.4 ± 5.4 years and 8.2 ± 0.8%, respectively; ~80% of participants were aged ≥70 years; 80% had macrovascular complications, one third had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 ; and half had been diagnosed with diabetes for >15 years. Linagliptin significantly improved glucose control at 24 weeks (HbA1c-adjusted mean change vs. placebo: -0.63%; P <0.0001) and the probability of achieving predefined HbA1c targets without hypoglycaemia (HbA1c <8.0%: OR 2.02; P <0.05 and HbA1c <7.0%: OR 2.44; P <0.01). Linagliptin versus placebo was well tolerated, with similar incidences of AEs, including clinically important hypoglycaemia (blood glucose <54 mg/dL) or severe hypoglycaemia. CONCLUSIONS: Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.

12.
Circ Heart Fail ; 12(6): e005875, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31163986

RESUMO

Background In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin significantly reduced the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus and established cardiovascular disease. Post hoc, we evaluated empagliflozin on kidney outcomes in patients with or without heart failure (HF). Methods and Results Individuals were randomized to empagliflozin 10 mg, 25 mg, or placebo. Prespecified analyses by baseline HF status included risk of incident or worsening nephropathy and estimated glomerular filtration rate slope analyses. Cox proportional hazards models assessed consistency of treatment effect across subgroups. Safety evaluations included kidney-related adverse events. At baseline, 244 (10.5%) and 462 (9.9%) patients had HF in the placebo and empagliflozin groups, respectively. Overall, the incidence of kidney outcome events was numerically higher in patients with than without HF. In the HF group, empagliflozin reduced risk of incident or worsening nephropathy or cardiovascular death by 43% (hazard ratio, 0.57 [95% CI, 0.42-0.77]) and progression to macroalbuminuria by 50% (hazard ratio, 0.50 [0.33-0.75]). After an initial transient decrease, estimated glomerular filtration rate stabilized over time with empagliflozin but gradually declined with placebo. Kidney effects in patients with HF were consistent with those in the overall study population (all P values for interaction >0.05). Across groups, the incidence rate of kidney-related adverse events/100 patient-years was higher in patients with than without HF; however, overall rates were comparable between groups. Conclusions These findings from EMPA-REG OUTCOME support the hypothesis that empagliflozin could reduce the risk of clinically relevant kidney events and may slow progression of chronic kidney disease in individuals with type 2 diabetes mellitus regardless of HF status. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Adulto , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
13.
Kidney Int ; 96(2): 489-504, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31142441

RESUMO

In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.

14.
Proteomics Clin Appl ; 13(2): e1800144, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632692

RESUMO

PURPOSE: Chronic kidney disease (CKD) is a serious complication of hyperglycemia and treatment options to slow its progression are scarce. Dipeptidyl peptidase-4 (DPP-4) inhibitors are common glucose-lowering drugs in type 2 diabetes (T2D). Among these, linagliptin has been suggested to exert kidney protective effects. It is investigated whether an effect of linagliptin on kidney function could be unmasked by characterizing the urinary proteome profile (UPP) in albuminuric T2D individuals. EXPERIMENTAL DESIGN: Participants of the MARLINA-T2D trial (NCT01792518) are randomized 1:1 to receive either linagliptin 5 mg or placebo for 24 weeks. A previously developed proteome-based classifier, CKD273, is assessed. RESULTS: Results confirm a significant correlation between CKD273 and clinical kidney parameters as well as with eGFR decline. Patient stratification using CKD273 at baseline, show a trend toward attenuation of renal function loss in high CKD-risk patients treated with linagliptin. Moreover, characterized are linagliptin affected peptides of which the majority contained a DPP-4 target sequence. CONCLUSIONS AND CLINICAL RELEVANCE: CKD273 is a promising tool for identifying patients at high risk for CKD progression and may unmask a potential of linagliptin to slow progressive kidney function loss in high CKD-risk patients. UPP characterization reveals a significant impact of linagliptin on urinary peptides.


Assuntos
Dipeptidil Peptidase 4/urina , Inibidores da Dipeptidil Peptidase IV/farmacologia , Rim/efeitos dos fármacos , Linagliptina/farmacologia , Proteômica , Feminino , Humanos , Masculino
15.
Circulation ; 139(3): 351-361, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30586723

RESUMO

BACKGROUND: Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and/or kidney disease. METHODS: Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction > or ≤50%. RESULTS: CARMELINA enrolled 6979 participants (mean age, 65.9 years; estimated glomerular filtration rate, mL/min per 1.73m2; hemoglobin A1c, 8.0%; 62.9% men; diabetes mellitus duration, 14.8 years), including 1873 (26.8%) with a history of HF at baseline. Median follow-up was 2.2 years. Linagliptin versus placebo did not affect the incidence of hHF (209/3494 [6.0%] versus 226/3485 [6.5%], respectively; hazard ratio [HR], 0.90; 95% CI, 0.74-1.08), the composite of cardiovascular death/hHF (HR, 0.94; 95% CI, 0.82-1.08), or risk for recurrent hHF events (326 versus 359 events, respectively; rate ratio, 0.94; 95% CI, 0.75-1.20). There was no heterogeneity of linagliptin effects on hHF by history of HF at baseline, baseline estimated glomerular filtration rate or urine albumin-creatinine ratio, or prerandomization left ventricular ejection fraction. CONCLUSIONS: In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01897532.


Assuntos
Aterosclerose/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/epidemiologia , Nefropatias/epidemiologia , Linagliptina/uso terapêutico , Idoso , Aterosclerose/diagnóstico , Aterosclerose/mortalidade , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Humanos , Rim/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/mortalidade , Nefropatias/fisiopatologia , Linagliptina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
J Hypertens ; 37(6): 1294-1300, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30540657

RESUMO

OBJECTIVE: Concomitant treatment with angiotensin-converting enzyme (ACE) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors is increasingly common. Pharmacological studies have suggested a potential adverse drug interaction between ACE inhibitors and DPP-4 inhibitors resulting in unfavorable hemodynamic changes; very few studies have examined such an interaction between angiotensin II receptor blockers (ARBs) and DPP-4 inhibitors. We investigated blood pressure (BP) and heart rate (HR) during treatment with the DPP-4 inhibitor linagliptin in individuals receiving either ACE inhibitors or ARBs in the MARLINA-T2D trial. METHODS: In this study, 360 individuals with type 2 diabetes and albuminuria receiving unchanged doses of ACE inhibitors or ARBs were randomized to linagliptin or placebo. Twenty-four-hour ambulatory BP monitoring, an exploratory endpoint, was conducted at baseline and after 24 weeks. RESULTS: Ambulatory BP monitoring data were available for 208 individuals (linagliptin: n = 111; placebo: n = 97). Baseline mean ±â€ŠSD 24-h SBP and DBP were 132.5 ±â€Š12.4 mmHg and 75.9 ±â€Š9.4 mmHg, respectively; mean 24-h HR was 76.3 ±â€Š10.1 bpm. At week 24, no overall effect of the DPP-4 inhibitor versus placebo was seen on mean 24-h SBP, DBP, or HR. Furthermore, in the subgroups receiving either an ACE inhibitor or an ARB, no effect on these hemodynamic parameters was seen as a result of concomitant DPP-4 inhibitor treatment. CONCLUSION: Adding linagliptin to treatment with ACE inhibitors or ARBs was not associated with any hemodynamic changes, supporting their concomitant use in individuals with type 2 diabetes and albuminuria.

17.
JAMA ; 321(1): 69-79, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418475

RESUMO

Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Linagliptina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco
18.
J Diabetes Investig ; 10(3): 760-770, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30412655

RESUMO

AIMS/INTRODUCTION: In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. MATERIALS AND METHODS: Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. RESULTS: Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49-0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49-0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25-0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. CONCLUSIONS: In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Albuminúria/etiologia , Albuminúria/patologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Biomarcadores/análise , Glicemia/análise , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Seguimentos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Prognóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Fatores de Risco
19.
Clin Kidney J ; 11(6): 749-761, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30524708

RESUMO

Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA