Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
1.
Lancet Diabetes Endocrinol ; 8(12): 949-959, 2020 Dec.
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.

2.
Diabetes Obes Metab ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33185002

RESUMO

AIMS: Safety is a key consideration for glucose-lowering agents for older people with type 2 diabetes, yet comparative data are limited. We compared the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both pre-specified and post-hoc analyses. MATERIALS AND METHODS: People aged 40-85 years with relatively early type 2 diabetes, inadequate glycaemic control, and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1-4 mg. The primary endpoint was time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE). We evaluated clinical and safety outcomes across age. RESULTS: Of 6033 participants, 50.7% were aged <65 years, 35.3% were 65-74, and 14.0% were ≥75. During 6.3-year median follow-up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for 3-point MACE 0.98 [95.47% CI 0.84,1.14]) or across age groups (interaction P>0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate-to-severe hypoglycaemia was markedly reduced with linagliptin (HR=0.18 [95% CI 0.15,0.21]) with no differences among age groups (P=0.23). Mean weight was -1.54 kg (95% CI -1.80,-1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin. CONCLUSIONS: Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk for hypoglycaemia and falls or fractures than glimepiride, including in "older-old" individuals for whom these are particularly important treatment considerations. This article is protected by copyright. All rights reserved.

3.
Am Heart J ; 232: 10-22, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33214130

RESUMO

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) use is associated with improved cardiovascular and kidney outcomes. However, the magnitude and potential heterogeneity of effect across patients with varying types of cardiometabolic and kidney disease is unclear. To examine the effect of SGLT2i on cardiovascular and kidney outcomes among patients with type 2 diabetes mellitus (T2DM), and independent of T2DM status, among patients with heart failure (HF), and chronic kidney disease. METHOD: Medline, Embase, Cochrane library and scientific conferences were searched from inception till September 24, 2020 for randomized controlled trials comparing cardiovascular and kidney outcomes between SGLT2i and placebo. Random effects hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: Eight trials with a combined 59,747 patients were included. In the overall population, SGLT2i reduced the risk of all-cause mortality (HR 0.84; 95% CI [0.78-0.91]), cardiovascular mortality (HR 0.84; 95% CI [0.76-0.93]) hospitalization for HF (HR 0.69; 95% CI [0.64-0.74]), myocardial infarction (HR 0.91; 95% CI [0.84-0.99]), and composite kidney outcome (HR 0.62; 95% CI [0.56-0.70]). There was no significant effect on the risk of stroke (HR 0.98; 95% CI [0.86-1.11]). Results were consistent across subgroups stratified by diabetes and HF status. SGLT2i use was not associated with a greater risk of hypoglycemia (OR 0.92; 95% CI [0.84-1.01]) or amputation (OR 1.25; 95% CI [0.97-1.62]). There were 64 diabetic ketoacidosis events with SGLT2i use and 18 with placebo (OR 2.86; 95% CI [1.39-5.86]). CONCLUSIONS: In patients with cardiometabolic and kidney disease, SGLT2i improved cardiovascular and kidney outcomes, regardless of T2DM, HF, and/or CKD status. The magnitude of risk reduction was largest for hospitalization for HF and progression of kidney disease, more modest for mortality and MI and absent for stroke.

4.
JAMA ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33190147

RESUMO

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

6.
Circulation ; 142(20): 1885-1886, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33196310
8.
N Engl J Med ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33200891

RESUMO

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).

9.
N Engl J Med ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33200892

RESUMO

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. METHODS: We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. RESULTS: A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. CONCLUSIONS: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).

10.
JAMA Cardiol ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33031522

RESUMO

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain. Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes. Data Sources: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020. Study Selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials. Data Extraction and Synthesis: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model. Main Outcomes and Measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials. Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction). Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

11.
Diabetes ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106255

RESUMO

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33063112

RESUMO

AIMS: Concomitant atrial fibrillation (AF) and diabetes mellitus (DM) increases risk of stroke and systemic embolic events. This meta-analysis assessed the benefit/risk balance of non-vitamin K antagonist oral anticoagulants (NOACs) vs warfarin, and explored whether there was effect modification by DM or heterogeneity in outcomes between NOACs in patients with and without DM. METHODS: We performed a meta-analysis of 58,634 patients from four phase 3 trials of NOAC vs warfarin in patients with AF, comparing the primary outcomes of efficacy and safety and 6 other secondary outcomes in patients stratified by the presence of DM. Interaction testing was used to assess for heterogeneity of treatment effects. A meta-regression was performed to evaluate the influence of baseline characteristics. RESULTS: NOACs reduced the risk of stroke/SEE in 18,134 patients with DM [hazard ratio (HR) 0.80; 95% confidence interval (CI) (0.69-0.93), I2 3.90] to a similar degree as in 40,500 patients without DM [HR 0.82; 95% CI (0.74-0.91)], I2 16.33 p-int 0.81). There was no effect modification of DM on the relative reduction with NOACs vs warfarin in major bleeding (DM : 0.95, 95% CI 0.75-1.20, I2 43.83; no DM: 0.83, 95% CI 0.55-1.24; I2 87.90; p-int 0.37). Intracranial Haemorrhage (HRs 0.51 and 0.47, p-int 0.70) and cardiovascular death (HRs 0.87 and 0.90, p-int 0.70) were significantly reduced by NOACs in the presence or absence of DM. CONCLUSION: NOACs are more effective and safer than warfarin in AF patients with or without DM and absent contraindications, NOACs should be the anticoagulation treatment choice in diabetics.

13.
Am J Kidney Dis ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33121838

RESUMO

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

14.
Circulation ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026243

RESUMO

Background: In patients with type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. Methods: VERTIS CV, a double-blind, placebo-controlled trial, randomized patients with T2DM and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazard modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events. Results: 8246 patients were randomized to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pre-trial ejection fraction (EF) available, including n=959 with EF≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (HR, 0.88; 95% CI, 0.75, 1.03). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70; 95% CI, 0.54, 0.90; P=0.006). Prior HF did not modify this effect (HF: HR, 0.63; 95% CI, 0.44, 0.90; no HF: HR, 0.79; 95% CI, 0.54, 1.15; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF≤45% vs preserved EF>45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF≤45% (HR, 0.48; 95% CI, 0.30, 0.76) versus EF>45% (HR, 0.86; 95% CI, 0.58, 1.29). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in three populations with baseline eGFR<60mL/min/1.73m2, albuminuria, and diuretic use (each P interaction<0.05). Ertugliflozin reduced total events of HHF (RR, 0.70; 95% CI, 0.56, 0.87) and total HHF/CV death (RR, 0.83; 95% CI, 0.72, 0.96). Conclusions: In patients with T2DM with or without baseline HF, ertugliflozin reduced risk for first and total HHF and total HHF/CV death, adding further support for the use of SGLT2 inhibitors in primary and secondary prevention of HHF. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01986881.

15.
Circulation ; 142(12): 1205-1218, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32955939

RESUMO

With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease- and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.

17.
Diabetes Care ; 43(11): 2684-2690, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32887711

RESUMO

OBJECTIVE: Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among patients with type 2 diabetes, but early uptake in practice appears restricted to particular demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries. RESEARCH DESIGN AND METHODS: We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of noninsulin antihyperglycemic therapies. We used 2012-2017 national and state Medicaid data to compare prescription claims and costs between states that did (n = 25) and did not expand (n = 26) Medicaid by January 2014. RESULTS: Following Medicaid expansion in 2014, average noninsulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in nonexpansion states. For sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA), quarterly growth rates per 1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for nonexpansion states, respectively. Expansion states had faster utilization of SGLT2i and GLP-1RA than nonexpansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion versus nonexpansion states was 1.68 (95% CI 1.09-2.26; P < 0.001) for all noninsulin therapies, 0.125 (-0.003 to 0.25; P = 0.056) for SGLT2i, and 0.12 (0.055-0.18; P < 0.001) for GLP-1RA. CONCLUSIONS: Use of noninsulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and nonexpansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.

18.
N Engl J Med ; 383(15): 1425-1435, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32966714

RESUMO

BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).


Assuntos
Aterosclerose/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Aterosclerose/complicações , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
19.
Diabetes Care ; 43(11): 2713-2720, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32928957

RESUMO

OBJECTIVE: To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS: Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in ß-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS: A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS: In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.

20.
Curr Cardiol Rep ; 22(10): 105, 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770420

RESUMO

PURPOSE OF REVIEW: Results from cardiovascular (CV) outcome trials have revealed important insights into the CV safety and efficacy of glucose-lowering agents, including dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). RECENT FINDINGS: Among patients with T2DM, DPP-4i have no significant effect on risk of major adverse CV events (MACE: CV death, myocardial infarction, or stroke) with mixed results regarding risk for heart failure (HF). While sitagliptin and linagliptin have neutral effects on HF risk, saxagliptin significantly increases the risk of HF. The CV safety of the GLP-1RA class of medications has been clearly demonstrated, and select agents, such as liraglutide, semaglutide, albiglutide, and dulaglutide, reduce the risk of MACE in patients with T2DM and established CV disease. CV outcome trials have demonstrated CV safety but not incremental efficacy for DPP-4i in most cases. Select GLP-1RA have proven efficacy for MACE and should be considered by cardiologists for CV risk mitigation in the care of patients with T2DM and established CV disease.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA